JPH04312572A - Cyclic amine compound - Google Patents

Abstract

PURPOSE:To obtain a new compound capable of exhibiting excellent anticerebral ischemic action as a therapeutic agent for cerebral edema. CONSTITUTION:A compound, e.g. 4-[4-(N,N-dimethylaminomethyl)- phenyl]piperidine expressed by formula I [R1 and R2 are 1-5C alkyl, etc.; R is H, 1-5C alkyl, etc.; X is methylene, etc.; (n) is 0-4; A is benzene ring] or its salt. The aforementioned compound is obtained by reacting a compound expressed by formula II with a compound expressed by the formula R3'-Z (R3' is alkyl, etc.; Z is group condensedly eliminative together with H at the 1-position of the piperidine ring).

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medicament, particularly an effective medicament for treating various symptoms associated with cerebral hypoxia and cerebral ischemia, particularly cerebral edema, and a novel cyclic amine compound useful for the production thereof.

0002

[Prior Art and Problems to be Solved by the Invention] Current measures to treat neoplastic substances in the brain, increased intracranial pressure due to traumatic pressure, and cerebral edema caused by cerebral ischemia include the administration of large amounts of steroid hormones. Although there are methods such as administration and osmotic pressure caused by ethylene glycol, there are currently no drugs that are satisfactory in terms of efficacy and side effects. An object of the present invention is to provide novel compounds that can be effective therapeutic agents for cerebral edema.

0003

[Means for Solving the Problems] As a result of intensive efforts by the present inventors to search for a compound useful as an ameliorating drug for the central nervous system, particularly for cerebral edema associated with cerebral ischemia, the present inventors found that the formula (I)

[
[In the formula, R1 and R2 each represent a C1-5 alkyl group, or together with the adjacent nitrogen atom, represent a cyclic amino group, and R3 has a hydrogen atom, a C1-5 alkyl group, or a substituent. phenyl-C1-5 which may have an alkyl group or diphenyl-C1-5 which may have a substituent
an alkyl group, X is a methylene group or a carbonyl group,
n is an integer of 0 to 4, ring A represents a benzene ring which may have a substituent] Creation of a cyclic amine compound [hereinafter sometimes simply referred to as compound (I)] and its salt They found that they exhibited excellent cerebral edema-improving effects, and after further study, they completed the present invention.

That is, the present invention provides a cyclic amine compound represented by the above formula (I), a salt thereof, and a therapeutic agent for cerebral edema, an agent for protecting brain/neural cells, and an agent for improving cerebral microcirculatory disorders, which are characterized by containing the same. agent (erythrocyte deformability) and/
or regarding drugs for acute stroke treatment.

In the formula, examples of the C1-5 alkyl group represented by R1, R2 and R3 include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, pentyl, and cyclopentyl groups. Examples of the phenyl-C1-5 alkyl group represented by R3 include phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, etc., and diphenyl-C1-
Examples of the 5-alkyl group include diphenylmethyl, diphenylethyl, diphenylpropyl, diphenylbutyl, diphenylpentyl, and the like. Also, R1 and R2
Cyclic amino groups formed together with adjacent nitrogen atoms include pyrrolidino, piperidino, hexamethyleneimino, thiazolidino, N-phenylpiperazino, N-methylpiperazino, morpholino, etc. In addition to nitrogen atoms, sulfur atoms, oxygen Examples include 5- or 6-membered cyclic amino groups which may contain 1 to 3 heteroatoms such as atoms. “Optionally substituted phenyl-” represented by R3
As a substituent of "C1-5 alkyl group, diphenyl-C1-5 alkyl group which may have a substituent,"
3-alkyloxy (e.g., methyloxy, ethyloxy, propyloxy, etc.), C1-3 alkylamino (e.g., methylamino, ethylamino, propylamino, etc.), C1-3 dialkylamino (e.g., dimethylamino, diethylamino, dipropyl) amino, ethylmethylamino, ethylpropylamino, etc.), C1-3 alkyl (e.g. methyl, ethyl, propyl, etc.), halogen (
fluorine, chlorine, bromine, iodine), cyano group, nitro group,
Carboxyl group, C1-3 alkyloxycarbonyl (
Examples include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, etc., and 1 to 3 of these may be substituted.

[0006] Furthermore, as a substituent for ring A, halogen (
fluorine, chlorine, bromine, iodine), C1- as mentioned above
5 alkyl group, C1-5 alkoxy group (for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, etc.), and one or two of these may be substituted. Preferred embodiments of the compound represented by the above formula (I) include, for example, the following. R1 and R2 are preferably C1-3 alkyl groups, particularly methyl and ethyl groups. R3 is preferably a diphenyl-C1-5 alkyl group, a C1-5 alkyl group, or a hydrogen atom, which may have a substituent, particularly a diphenylmethyl group,
A methyl group, an ethyl group, and a hydrogen atom are preferred. X is preferably a methylene group. n is preferably 0 or 1. Also, X
However, those with a methylene group are particularly effective in improving cerebral edema, and
Those in which X is a carbonyl group are also useful as intermediates for the production of those in which X is a methylene group.

The compound (I) of the present invention may form acid addition salts, especially physiologically acceptable acid addition salts, such as inorganic salts (eg, hydrochloric acid, sulfuric acid, etc.). , nitric acid, phosphoric acid, hydrobromic acid, etc.), or organic acids (such as acetic acid, propionic acid, fumaric acid, maleic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid,
Methanesulfonic acid, benzenesulfonic acid, etc.).

The method for producing the compound of the present invention will be explained below. Among compound (I) or a salt thereof, formula (Ib)

[chemical 8
[In the formula, R3' is a C1-5 alkyl group, a phenyl-C1-5 alkyl group that may have a substituent, or a diphenyl-C1-5 alkyl group that may have a substituent, and has the same meaning as above] or a salt thereof has the formula (Ia)

[Symbols in the formula have the same meanings as above] or a salt thereof and the formula R3'-Z (A
) [In the formula, R3' has the same meaning as above, and Z represents a group that is condensed and eliminated together with the hydrogen atom at the 1-position of the piperidine ring]. can. As the salt of compound (Ia), the above compound (
Salts such as those mentioned in I) are used. In the above formula, R3
The group represented by ' is C1 as described above for R3.
-5 alkyl group, phenyl which may have a substituent -
A C1-5 alkyl group or a diphenyl-C1-5 alkyl group which may have a substituent is used. Z in compound (A) represents a group that condensates and leaves together with the hydrogen atom at the 1-position of the piperidine ring of compound (Ia), and specifically, it represents a group that condensates and leaves the hydrogen atom such as chlorine, bromine, iodine, etc., toluenesulfonyloxy, etc. An arylsulfonyloxy group, an alkylsulfonyloxy group such as methanesulfonyloxy, etc. are used. This reaction can be carried out using protic solvents (e.g., water, alcohols such as methanol, ethanol, propanol, etc.), aprotic solvents (e.g., ethers such as ethyl ether, tetrahydrofuran, dioxane, amides such as dimethylformamide, acetonitrile, etc.). If necessary, organic bases such as pyridine, 4-dimethylaminopyridine, triethylamine, triethylenediamine, and tetramethylethylenediamine, and sodium bicarbonate, potassium bicarbonate, The reaction can be advantageously carried out in the presence of an inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, etc. Compound represented by formula (Ia) or a salt thereof The compound represented by formula (A) is usually used in an amount of about 1 to 10 moles, preferably about 1 to 2 moles, per 1 mole.The reaction time is usually about 1 hour to 48 hours.
Preferably it is about 10 hours to 20 hours, and the reaction temperature is -10°C to 200°C, preferably 20°C to 100°C.

[0009] Also, among compound (I) or a salt thereof,
Formula (Ic)

[Symbols in the formula have the same meanings as above] A compound or a salt thereof represented by the formula

[In the formula, R1, R2, n and A ring have the same meanings as above,
R4 is a hydrogen atom, C1-5 alkyl, phenyl-C1-5 alkyl group which may have a substituent, diphenyl-C1-5 alkyl group which may have a substituent, or the formula R5-CO-( In the formula, R5 is a hydrogen atom, a C1-4 alkyl group, an optionally substituted phenyl-C1-4 alkyl group, or an optionally substituted diphenyl-
C1-4 alkyl group)] or a salt thereof.

In the formula, R4 represents a C1-5 alkyl group, a phenyl-C1-5 alkyl group which may have a substituent, and a diphenyl-C1 which may have a substituent.
As the -5 alkyl group, those mentioned for R3 above are used. Examples of the C1-4 alkyl group represented by R5 include methyl, ethyl, propyl, butyl, isopropyl, and isobutyl. Examples of the phenyl-C1-4 alkyl group represented by R5 include phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, etc., and examples of the diphenyl-C1-4 alkyl group include diphenylmethyl, diphenylethyl,
Diphenylpropyl, diphenylbutyl, etc. are used. In addition, the substituents in the “phenyl C1-4 alkyl group which may have a substituent” and “diphenyl-C1-4 alkyl group which may have a substituent” represented by R5 include the above-mentioned R3 The same substituents as "phenyl-C1-5 alkyl group which may have a substituent, diphenyl-C1-5 alkyl group which may have a substituent" may be used. Moreover, as the salt of compound (Id), the same salt as the salt of compound (I) can be used. This reaction is carried out in a solvent. As the solvent, for example, aprotic solvents such as diethyl ether, tetrahydrofuran, and dioxane are used. As the reducing agent, lithium aluminum hydride, diborane, etc. are preferably used. −
It can be carried out at about 10°C to 200°C, preferably about 20°C to 100°C. The amount of reducing agent used is the compound (Id)
or 0.5 to 5 mol, preferably 1 to 2 mol, per mol of the salt. The reaction time is usually 0.5 to 24 hours, preferably 2 to 5 hours.

When the compound represented by formula (Ia) or a salt thereof is X=methylene group, the compound (Id) (R
4 = hydrogen atom) or its salt, and in the case of X = carbonyl group, for example, reaction formula 1

[Chemical formula 12]

[In the formula, R1, R2, n and ring A have the same meanings as defined above], a compound represented by formula (II) and a compound represented by formula (II
Formula (IV) obtained by reacting with the compound represented by I)
) [where n' is an integer of 1 to 4, R
6 represents a C1-4 alkyl group, such as a methyl, ethyl, propyl, butyl group, etc.] or a formula obtained by reacting a compound represented by formula (II) with a compound represented by formula (III') Compound represented by (IV') [wherein Y represents halogen (fluorine, chlorine, bromine and iodine)]
A compound represented by the formula (IV'') derived from the formula (V
) or the compound represented by formula (V') or formula (VI), then the compound represented by formula (VII) [wherein R4' is an amino protecting group,
For example, t-butyloxycarbonyl, benzyloxycarbonyl group, etc.] is derived, and the formula (
VIII) [wherein R1, R2, and R4' have the same meanings as above. ] It can be produced through the compound represented by.

A compound represented by formula (II) and a compound represented by formula (I
The reaction with the compound represented by II) or formula (III') can be carried out by a method known per se. For example, a compound represented by formula (II) and formula (III) or formula (
The reaction can be carried out by reacting the compound represented by III') without using a solvent or in a solvent, if necessary in the presence of an acid or the like. Examples of the acid include so-called Lewis acids, such as aluminum chloride, zinc chloride, titanium chloride, and the like. The solvent may be any solvent commonly used in chemical reactions as long as it does not interfere with the reaction, for example, dichloromethane, dichloroethane, nitrobenzene, carbon disulfide, etc.
It can be carried out at a temperature of about 0°C, preferably about 20°C to 100°C. Usually, about 1 to 20 mol, preferably about 2 to 20 mol of the compound represented by formula (III) or formula (III') is added to 1 mol of the compound represented by formula (II).
A 5 molar amount is used. The reaction time is usually 1 to 48 hours, preferably 5 to 10 hours. The reaction leading from the compound represented by formula (IV') to the compound represented by formula (IV') is
For example, a compound represented by formula (IV') in a protic solvent (e.g., water, methanol, ethanol, propanol, etc.) or an aprotic solvent (e.g., dioxane, dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, etc.), It can be produced by reacting cuprous cyanide or the like. The reaction temperature is 50℃~
It can be carried out at 300°C, preferably 100°C to 200°C. Usually, 0.5 to 3 mol, preferably 1 mol of cuprous cyanide is added to 1 mol of the compound represented by formula (IV').
~1.5 molar amount is used. The reaction time is 1 to 48 hours, preferably 10 to 20 hours.

The reaction leading to the compound represented by formula (V) or formula (V') from the compound represented by formula (IV) or formula (IV'') can also be carried out by a method known per se. IV) or by reacting an acid or base with a compound represented by formula (IV") (V)
Or obtain (V'). Examples of acids include mineral acids (for example, nitric acid, hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, etc.), and bases include alkali metal hydroxides (for example, sodium hydroxide, potassium hydroxide, barium hydroxide, water, etc.). lithium oxide, etc.), and these acids or bases are used as ordinary aqueous solutions. The reaction can be carried out at a temperature of 10° to 150°C, preferably 50°C to 100°C. Usually, 10 to 100 equivalents of acid or base, preferably 2 equivalents, are added to the compound represented by formula (IV) or formula (IV').
0 to 40 equivalents are used. The strength of the acid and base is preferably around 1N to 10N, preferably 4N to 10N. The reaction time depends on the reaction temperature, but is usually about 1 hour to 24 hours, preferably about 2 hours to 10 hours.

The reaction leading to the compound represented by formula (VI) from the compound represented by formula (V) or formula (V') is as follows:
This can be carried out by a reduction reaction known per se. For example, it can be produced by catalytically reducing a compound represented by formula (V) or formula (V') in a solvent in the presence of a catalyst. As the solvent, any solvent commonly used in chemical reactions may be used as long as it does not interfere with the reaction, such as water, methanol, ethanol, dimethylformamide, tetrahydrofuran, and dioxane. As the catalyst, a palladium-based, rhodium-based, platinum-based, or Raney nickel-based catalyst is used. The reaction can be carried out at about -10°C to 100°C, preferably about 20°C to 50°C, under a hydrogen pressure of 1 atm to 100 atm, preferably 1 atm to 5 atm, and if necessary in the presence of an acid. Examples of acids used include mineral acids (e.g., hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid) or organic acids (e.g., acetic acid, propionic acid, tartaric acid, benzoic acid, methanesulfonic acid, toluenesulfonic acid). . The reaction time is usually 1
~24 hours, preferably 2 to 5 hours.

The compound represented by formula (VII) is a compound represented by formula (VII).
VI) in a protic solvent (e.g., water, methanol, ethanol, propanol, etc.) or an aprotic solvent (e.g., ethyl ether, tetrahydrofuran, dioxane, dimethylformamide, acetonitrile, etc.). Introducing a protective group for the group. For example, it can be obtained by reacting with di-tert-butyl carbonate, carbobenzoxy chloride, or the like. Furthermore, in order to advance this reaction advantageously, for example, pyridine, 4-dimethylaminopyridine, triethylamine,
The presence of organic bases such as triethylenediamine, tetramethylethylenediamine, and inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, etc. It can be done below. For 1 mole of the compound represented by formula (VI), ditertiary butyl carbonate, carbobenzoxy chloride, etc. are usually
It is used in an amount of about 1 to 10 moles, preferably about 1 to 2 moles. The reaction time is usually about 1 hour to 48 hours, preferably about 1 hour to 10 hours, and the reaction temperature is -10°C to 200°C, preferably 0°C to 30°C.

The compound represented by formula (VIII) is a compound represented by formula (VII) and a compound represented by formula (IX).

[Chem.14
] The compound represented by the formula [wherein R1 and R2 have the same meanings as above] can be obtained by forming an amide bond with diethyl cyanophosphate, dicyclohexylcarbodiimide, N-hydroxysuccinimide, a mixture thereof, or the like. The solvent used may be any solvent commonly used in chemical reactions as long as it does not interfere with the reaction, such as ether solvents such as ethyl ether, tetrabitrofuran, dioxane, dichloroethane, chloroform, dichloroethane, carbon tetrachloride, etc. Examples include halogenated solvents, hydrocarbon solvents such as hexane, benzene, toluene, and xylene, dimethylformamide, and dimethylsulfoxide. The compound represented by formula (IX) and diethyl cyanophosphate, disiloxhexylcarbodiimide, N-hydroxysuccinimide, etc. are usually 1 to 5 mol each, preferably 1 to 5 mol, per 1 mol of the compound represented by formula (VIII). 1.5 mol is used. Moreover, the reaction temperature can be carried out at -20°C to 50°C, preferably 0°C to 20°C.

The compound represented by formula (Ie) is a compound represented by formula (V
It can be obtained by contacting the compound represented by III) with an acid in a conventional manner or by subjecting it to catalytic reduction. Examples of acids used include trifluoroacetic acid, mineral acids (eg, nitric acid, hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid), hydrogen chloride, and the like. Moreover, catalytic reduction can be performed using a solvent. As the solvent, any solvent commonly used in chemical reactions may be used as long as it does not interfere with the reaction, such as water, methanol, ethanol, dimethylformamide, tetrahydrofuran, dioxane, and the like. As the catalyst, for example, a palladium-based, rhodium-based, platinum-based, or Raney nickel-based catalyst is used. The reaction is carried out at -10°C to 100°C, preferably at 0°C.
The reaction is carried out at a temperature of about 30° C. and under a hydrogen pressure of 1 atm to 100 atm, preferably 1 atm to 5 atm. The reduction can also advantageously be carried out in the presence of an acid. Examples of the acids used include mineral acids (e.g., hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid) or organic acids (e.g., acetic acid, propionic acid, tartaric acid, benzoic acid, methanesulfonic acid, toluenesulfonic acid). It will be done. Reduction reaction time is usually 0.5 to 10 hours,
Preferably it is 1 to 3 hours. In addition, when R4=hydrogen atom, the compound (Id) or a salt thereof may be the compound (Id) or a salt thereof.
It can be produced according to the production method of Ic), and R4=C
In the case of a 1-5 alkyl group, an optionally substituted phenyl-C1-5 alkyl group, or an optionally substituted diphenyl-C1-5 alkyl group, the compound (Ia) (X = carbonyl group), that is, the compound (
Ie) or a salt thereof and compound (A), and when R4=R5-CO-, compound (Ie) or a salt thereof and formula (X)

It can be obtained by reacting the compound represented by the formula [wherein R5 and Z have the same meanings as above]. Formula (Ie)
The reaction between the compound represented by formula (X) and the compound represented by formula (X) may be performed in a solvent. As the solvent, for example, any solvent commonly used in chemical reactions may be used as long as it does not interfere with the reaction, such as water, methanol, ethanol, dimethylformamide, tetrahydrofuran, dioxane, and the like.

Furthermore, in order to advance this reaction advantageously, organic bases such as pyridine, 4-dimethylaminopyridine, triethylamine, triethylenediamine, and tetramethylethylenediamine, and sodium bicarbonate, potassium bicarbonate, carbonate, etc. The reaction can be carried out in the presence of an inorganic base such as sodium, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydroxide, potassium hydroxide, etc. The compound represented by formula (X) is generally used in an amount of about 1 to 10 moles, preferably about 1 to 2 moles, per 1 mole of the compound represented by formula (Ie). The reaction time is usually about 1 hour to 48 hours, preferably about 1 hour to 10 hours, and the reaction temperature is -10°C to 200°C, preferably 0°C to 30°C.

The above compounds (II) to (X), (II
I') to (V') and (Ia) to (Ie) which form salts can also be used as salts formed according to conventional methods, and such salts include those mentioned above for compound (I). Tagotoki salt etc. are used. In addition, compounds (I), (Ia
)~(Ie), (IV)~(VIII), (IV')~
(V') or a salt thereof can be isolated and purified by known means such as concentration, liquid conversion, dissolution, extraction, fractional distillation, crystallization, recrystallization, chromatography, etc. The mixture may be provided as a raw material for the next reaction. Preferred compounds (I) included in the present invention synthesized in this manner include the following.

4-[4-(N,N-dimethylaminomethyl)phenylmethyl]piperidine 4-[4-(N,N-diethylaminomethyl)phenylmethyl]piperidine 4-[4-(N,N-dipropyl) aminomethyl)phenylmethyl]piperidine 4-[4-(N,N-dibutylaminomethyl)phenylmethyl]piperidine 4-[4-(N,N-diisopropylaminomethyl)phenylmethyl]piperidine 4-[4-(N ,N-diisobutylaminomethyl)phenylmethyl]piperidine 4-[4-(N,N-di-sec-butylaminomethyl)phenylmethyl]piperidine 4-[4-(N,N-dipentylaminomethyl)phenylmethyl] Piperidine 4-[4-(1-pyrrolidinylmethyl)phenylmethyl]piperidine 4-[4-(1-piperidinylmethyl)phenylmethyl]piperidine 4-[4-(hexamethyleneimin-1-ylmethyl)
phenylmethyl]piperidine 4-[4-(3-thiazolidinylmethyl)phenylmethyl]piperidine 4-[4-(4-methyl-1-piperazinylmethyl)phenylmethyl]piperidine 4-[4-(4 -phenyl-1-piperazinylmethyl)
phenylmethyl]piperidine 4-[4-(morpholinomethyl)phenylmethyl]piperidine

4-[4-[2-(N,N-dimethylamino)ethyl]phenylmethyl]piperidine 4-[4-[2-(N,N-diethylamino)ethyl]
phenylmethyl]piperidine 4-[4-[2-(N,N-dipropylamino)ethyl]phenylmethyl]piperidine 4-[4-[2-(N,N-dibutylamino)ethyl]
phenylmethyl]piperidine 4-[4-[2-(N,N-diisopropylamino)ethyl]phenylmethyl]piperidine 4-[4-[2-(N,N-diisobutylamino)ethyl]phenylmethyl]piperidine 4- [4-[2-(N,N-di-sec-butylamino)ethyl]phenylmethyl]piperidine 4-[4-[2-(N,N-dipentylamino)ethyl]phenylmethyl]piperidine 4-[4 -[2-(1-pyrrolidinyl)ethyl]phenylmethyl]piperidine 4-[4-[2-(1-piperidinyl)ethyl]phenylmethyl]piperidine 4-[4-[2-(hexamethyleneimin-1-yl) )
ethyl]phenylmethyl]piperidine 4-[4-[2-(3-thiazolidinyl)ethyl]phenylmethyl]piperidine 4-[4-[2-(4-methyl-1-piperazinyl)ethyl]phenylmethyl]piperidine 4-[ 4-[2-(4-phenyl-1-piperazinyl)
ethyl]phenylmethyl]piperidine 4-[4-(2-morpholinoethyl)phenylmethyl]
piperidine

4-[4-[3-(N,N-dimethylamino)propyl]phenylmethyl]piperidine 4-[4-
[3-(N,N-diethylamino)propyl]phenylmethyl]piperidine 4-[4-[3-(N,N-dipropylamino)propyl]phenylmethyl]piperidine 4-[4-[3-(N, N-dibutylamino)propyl]phenylmethyl]piperidine 4-[4-[3-(N,N-diisopropylamino)propyl]phenylmethyl]piperidine 4-[4-[3-(N,N-diisobutylamino)propyl ]Phenylmethyl]piperidine 4-[4-[3-(N,N-di-sec-butylamino)propyl]phenylmethyl]piperidine 4-[4-[3-(N,N-dipentylamino)propyl]phenyl methyl]piperidine 4-[4-[3-(1-pyrrolidinyl)propyl]phenylmethyl]piperidine 4-[4-[3-(1-piperidinyl)propyl]phenylmethyl]piperidine 4-[
4-[3-(hexamethyleneimin-1-yl)propyl]phenylmethyl]piperidine 4-[4-[3-(3-thiazolidinyl)propyl]phenylmethyl]piperidine 4-[4-[3-(4- Methyl-1-piperazinyl)propyl]phenylmethyl]piperidine 4-[4-[3-(4-phenyl-1-piperazinyl)
propyl]phenylmethyl]piperidine 4-[4-(3-morpholinopropyl)phenylmethyl]piperidine

4-[4-[4-(N,N-dimethylamino)butyl]phenylmethyl]piperidine 4-[4-[4-(N,N-diethylamino)butyl]
phenylmethyl]piperidine 4-[4-[4-(N,N-dipropylamino)butyl]phenylmethyl]piperidine 4-[4-[4-(N,N-dibutylamino)butyl]
phenylmethyl]piperidine 4-[4-[4-(N,N-diisopropylamino)butyl]phenylmethyl]piperidine 4-[4-[4-(N,N-diisobutylamino)butyl]phenylmethyl]piperidine 4- [4-[4-(N,N-di-sec-butylamino)butyl]phenylmethyl]piperidine 4-[4-[4-(N,N-dipentylamino)butyl]phenylmethyl]piperidine 4-[4 -[4-(1-pyrrolidinyl)butyl]phenylmethyl]piperidine 4-[4-[4-(1-piperidinyl)butyl]phenylmethyl]piperidine 4-[4-[4-(hexamethyleneimin-1-yl) )
butyl]phenylmethyl]piperidine 4-[4-[4-(3-thiazolidinyl)butyl]phenylmethyl]piperidine 4-[4-[4-(4-methyl-1-piperazinyl)butyl]phenylmethyl]piperidine 4- [4-[4-(4-phenyl-1-piperazinyl)
butyl]phenylmethyl]piperidine 4-[4-(4-morpholinobutyl)phenylmethyl]
piperidine

4-[4-[5-(N,N-dimethylamino)pentyl]phenylmethyl]piperidine 4-[4-
[5-(N,N-diethylamino)pentyl]phenylmethyl]piperidine 4-[4-[5-(N,N-dipropylamino)pentyl]phenylmethyl]piperidine 4-[4-[5-(N, N-dibutylamino)pentyl]phenylmethyl]piperidine 4-[4-[5-(N,N-diisopropylamino)pentyl]phenylmethyl]piperidine 4-[4-[5-(N,N-diisobutylamino)pentyl ]Phenylmethyl]piperidine 4-[4-[5-(N,N-di-sec-butylamino)pentyl]phenylmethyl]piperidine 4-[4-[5-(N,N-dipentylamino)pentyl]phenyl methyl]piperidine 4-[4-[5-(1-pyrrolidinyl)pentyl]phenylmethyl]piperidine 4-[4-[5-(1-piperidinyl)pentyl]phenylmethyl]piperidine 4-[4-[5-( hexamethyleneimin-1-yl)
pentyl]phenylmethyl]piperidine 4-[4-[5-(3-thiazolidinyl)pentyl]phenylmethyl]piperidine 4-[4-[5-(4-methyl-1-piperazinyl)pentyl]phenylmethyl]piperidine 4-[ 4-[5-(4-phenyl-1-piperazinyl)
pentyl]phenylmethyl]piperidine 4-[4-(5-morpholinopentyl)phenylmethyl]piperidine

1-Methyl-4-[4-(N,N-dimethylaminomethyl)phenylmethyl]piperidine 1-methyl-4-[4-(N,N-diethylaminomethyl)phenylmethyl]piperidine 1-methyl- 4-[4-(N,N-dipropylaminomethyl)phenylmethyl]piperidine 1-methyl-4-[4-(N,N-dibutylaminomethyl)phenylmethyl]piperidine 1-methyl-4-[4- (N,N-diisopropylaminomethyl)phenylmethyl]piperidine 1-methyl-4-[4-(N,N-diisobutylaminomethyl)phenylmethyl]piperidine 1-methyl-4-[4-(N,N-diisobutylaminomethyl)phenylmethyl] -sec-butylaminomethyl)phenylmethyl]piperidine 1-methyl-4-[4-(N,N-dipentylaminomethyl)phenylmethyl]piperidine 1-methyl-4-[4-(1-pyrrolidinylmethyl) phenylmethyl]piperidine 1-methyl-4-[4-(1-piperidinylmethyl)phenylmethyl]piperidine 1-methyl-4-[4-(hexamethyleneimine-1-
ylmethyl)phenylmethyl]piperidine 1-methyl-
4-[4-(3-thiazolidinylmethyl)phenylmethyl]piperidine 1-methyl-4-[4-(4-methyl-1-piperazinylmethyl)phenylmethyl]piperidine 1-methyl-4-[4 -(4-phenyl-1-piperazinylmethyl)phenylmethyl]piperidine 1-methyl-
4-[4-(morpholinomethyl)phenylmethyl]piperidine

1-Methyl-4-[4-[2-(N,N-
dimethylamino)ethyl]phenylmethyl]piperidine 1-methyl-4-[4-[2-(N,N-diethylamino)ethyl]phenylmethyl]piperidine 1-methyl-4-[4-[2-(N,N -dipropylamino)ethyl]phenylmethyl]piperidine 1-methyl-4-[4-[2-(N,N-dibutylamino)ethyl]phenylmethyl]piperidine 1-methyl-4-[4-[2-( N,N-diisopropylamino)ethyl]phenylmethyl]piperidine 1-methyl-4-[4-[2-(N,N-diisobutylamino)ethyl]phenylmethyl]piperidine 1-methyl-4
-[4-[2-(N,N-di-sec-butylamino)
ethyl]phenylmethyl]piperidine 1-methyl-4-
[4-[2-(N,N-dipentylamino)ethyl]phenylmethyl]piperidine 1-methyl-4-[4-[2
-(1-pyrrolidinyl)ethyl]phenylmethyl]piperidine 1-methyl-4-[4-[2-(1-piperidinyl)ethyl]phenylmethyl]piperidine 1-methyl-4-[4-[2-(hexamethylene) imin-1-yl)ethyl]phenylmethyl]piperidine 1-
Methyl-4-[4-[2-(3-thiazolidinyl)ethyl]phenylmethyl]piperidine 1-methyl-4-[4-[2-(4-methyl-1-piperazinyl)ethyl]phenylmethyl]piperidine 1-methyl -4-[4-[2-(4-phenyl-1-piperazinyl)ethyl]phenylmethyl]piperidine 1-methyl-4-[4-(2-morpholinoethyl)phenylmethyl]piperidine

1-Methyl-4-[4-[3-(N,N-
dimethylamino)propyl]phenylmethyl]piperidine 1-methyl-4-[4-[3-(N,N-diethylamino)propyl]phenylmethyl]piperidine 1-methyl-4-[4-[3-(N,N -dipropylamino)propyl]phenylmethyl]piperidine 1-methyl-4-
[4-[3-(N,N-dibutylamino)propyl]phenylmethyl]piperidine 1-methyl-4-[4-[3
-(N,N-diisopropylamino)propyl]phenylmethyl]piperidine 1-methyl-4-[4-[3-(
N,N-diisobutylamino)propyl]phenylmethyl]piperidine 1-methyl-4-[4-[3-(N,N
-di-sec-butylamino)propyl]phenylmethyl]piperidine 1-methyl-4-[4-[3-(N,N
-dipentylamino)propyl]phenylmethyl]piperidine 1-methyl-4-[4-[3-(1-pyrrolidinyl)propyl]phenylmethyl]piperidine 1-methyl-4-[4-[3-(1-piperidinyl) propyl]phenylmethyl]piperidine 1-methyl-4-[4-[3-(hexamethyleneimin-1-yl)propyl]phenylmethyl]piperidine 1
-Methyl-4-[4-[3-(3-thiazolidinyl)propyl]phenylmethyl]piperidine 1-methyl-4-[4-[3-(4-methyl-1-piperazinyl)propyl]phenylmethyl]piperidine 1-
Methyl-4-[4-[3-(4-phenyl-1-piperazinyl)propyl]phenylmethyl]piperidine 1-methyl-4-[4-(3-morpholinopropyl)phenylmethyl]piperidine

1-Methyl-4-[4-[4-(N,N-
dimethylamino)butyl]phenylmethyl]piperidine 1-methyl-4-[4-[4-(N,N-diethylamino)butyl]phenylmethyl]piperidine 1-methyl-4-[4-[4-(N,N -dipropylamino)butyl]phenylmethyl]piperidine 1-methyl-4-[4-[4-(N,N-dibutylamino)butyl]phenylmethyl]piperidine 1-methyl-4-[4-[4-( N,N-diisopropylamino)butyl]phenylmethyl]piperidine 1-methyl-4-[4-[4-(N,N-diisobutylamino)butyl]phenylmethyl]piperidine 1-methyl-4
-[4-[4-(N,N-di-sec-butylamino)
butyl]phenylmethyl]piperidine 1-methyl-4-
[4-[4-(N,N-dipentylamino)butyl]phenylmethyl]piperidine 1-methyl-4-[4-[4
-(1-pyrrolidinyl)butyl]phenylmethyl]piperidine 1-methyl-4-[4-[4-(1-piperidinyl)butyl]phenylmethyl]piperidine 1-methyl-4-[4-[4-(hexamethylene) imin-1-yl)butyl]phenylmethyl]piperidine 1-
Methyl-4-[4-[4-(3-thiazolidinyl)butyl]phenylmethyl]piperidine 1-methyl-4-[4-[4-(4-methyl-1-piperazinyl)butyl]phenylmethyl]piperidine 1- Methyl-4-[4-[4-(4-phenyl-1-piperazinyl)butyl]phenylmethyl]piperidine 1-methyl-4-[4-(4-morpholinobutyl)phenylmethyl]piperidine

1-Methyl-4-[4-[5-(N,N-
dimethylamino)pentyl]phenylmethyl]piperidine 1-methyl-4-[4-[5-(N,N-diethylamino)pentyl]phenylmethyl]piperidine 1-methyl-4-[4-[5-(N,N -dipropylamino)pentyl]phenylmethyl]piperidine 1-methyl-4-
[4-[5-(N,N-dibutylamino)pentyl]phenylmethyl]piperidine 1-methyl-4-[4-[5
-(N,N-diisopropylamino)pentyl]phenylmethyl]piperidine 1-methyl-4-[4-[5-(
N,N-diisobutylamino)pentyl]phenylmethyl]piperidine 1-methyl-4-[4-[5-(N,N
-di-sec-butylamino)pentyl]phenylmethyl]piperidine 1-methyl-4-[4-[5-(N,N
-dipentylamino)pentyl]phenylmethyl]piperidine 1-methyl-4-[4-[5-(1-pyrrolidinyl)pentyl]phenylmethyl]piperidine 1-methyl-4-[4-[5-(1-piperidinyl) pentyl]phenylmethyl]piperidine 1-methyl-4-[4-[5-(hexamethyleneimin-1-yl)pentyl]phenylmethyl]piperidine 1
-Methyl-4-[4-[5-(3-thiazolidinyl)pentyl]phenylmethyl]piperidine 1-methyl-4-[4-[5-(4-methyl-1-piperazinyl)pentyl]phenylmethyl]piperidine 1 −
Methyl-4-[4-[5-(4-phenyl-1-piperazinyl)pentyl]phenylmethyl]piperidine 1-methyl-4-[4-(5-morpholinopentyl)phenylmethyl]piperidine

1-Ethyl-4-[4-(N,N-dimethylaminomethyl)phenylmethyl]piperidine 1-ethyl-4-[4-(N,N-diethylaminomethyl)phenylmethyl]piperidine 1-ethyl- 4-[4-(N,N-dipropylaminomethyl)phenylmethyl]piperidine 1-ethyl-4-[4-(N,N-dibutylaminomethyl)phenylmethyl]piperidine 1-ethyl-4-[4- (N,N-diisopropylaminomethyl)phenylmethyl]piperidine 1-ethyl-4-[4-(N,N-diisobutylaminomethyl)phenylmethyl]piperidine 1-ethyl-4-[4-(N,N-diisobutylaminomethyl)phenylmethyl] -sec-butylaminomethyl)phenylmethyl]piperidine 1-ethyl-4-[4-(N,N-dipentylaminomethyl)phenylmethyl]piperidine 1-ethyl-4-[4-(1-pyrrolidinylmethyl) phenylmethyl]piperidine 1-ethyl-4-[4-(1-piperidinylmethyl)phenylmethyl]piperidine 1-ethyl-4-[4-(hexamethyleneimine-1-
ylmethyl)phenylmethyl]piperidine 1-ethyl-
4-[4-(3-thiazolidinylmethyl)phenylmethyl]piperidine 1-ethyl-4-[4-(4-methyl-1-piperazinylmethyl)phenylmethyl]piperidine 1-ethyl-4-[4 -(4-phenyl-1-piperazinylmethyl)phenylmethyl]piperidine 1-ethyl-
4-[4-(morpholinomethyl)phenylmethyl]piperidine

1-Ethyl-4-[4-[2-(N,N-
dimethylamino)ethyl]phenylmethyl]piperidine 1-ethyl-4-[4-[2-(N,N-diethylamino)ethyl]phenylmethyl]piperidine 1-ethyl-4-[4-[2-(N,N -dipropylamino)ethyl]phenylmethyl]piperidine 1-ethyl-4-[4-[2-(N,N-dibutylamino)ethyl]phenylmethyl]piperidine 1-ethyl-4-[4-[2-( N,N-diisopropylamino)ethyl]phenylmethyl]piperidine 1-ethyl-4-[4-[2-(N,N-diisobutylamino)ethyl]phenylmethyl]piperidine 1-ethyl-4
-[4-[2-(N,N-di-sec-butylamino)
ethyl]phenylmethyl]piperidine 1-ethyl-4-
[4-[2-(N,N-dipentylamino)ethyl]phenylmethyl]piperidine 1-ethyl-4-[4-[2
-(1-pyrrolidinyl)ethyl]phenylmethyl]piperidine 1-ethyl-4-[4-[2-(1-piperidinyl)ethyl]phenylmethyl]piperidine 1-ethyl-4-[4-[2-(hexamethylene) imin-1-yl)ethyl]phenylmethyl]piperidine 1-
Ethyl-4-[4-[2-(3-thiazolidinyl)ethyl]phenylmethyl]piperidine 1-ethyl-4-[4-[2-(4-methyl-1-piperazinyl)ethyl]phenylmethyl]piperidine 1-ethyl -4-[4-[2-(4-phenyl-1-piperazinyl)ethyl]phenylmethyl]piperidine 1-ethyl-4-[4-(2-morpholinoethyl)phenylmethyl]piperidine

1-Ethyl-4-[4-[3-(N,N-
dimethylamino)propyl]phenylmethyl]piperidine 1-ethyl-4-[4-[3-(N,N-diethylamino)propyl]phenylmethyl]piperidine 1-ethyl-4-[4-[3-(N,N -dipropylamino)propyl]phenylmethyl]piperidine 1-ethyl-4-
[4-[3-(N,N-dibutylamino)propyl]phenylmethyl]piperidine 1-ethyl-4-[4-[3-(N,N
-diisopropylamino)propyl]phenylmethyl]
piperidine 1-ethyl-4-[4-[3-(N,N-diisobutylamino)propyl]phenylmethyl]piperidine 1-ethyl-4-[4-[3-(N,N-di-sec-butylamino) ) propyl]phenylmethyl]piperidine 1-ethyl-4-[4-[3-(N,N-dipentylamino)
propyl]phenylmethyl]piperidine 1-ethyl-4
-[4-[3-(1-pyrrolidinyl)propyl]phenylmethyl]piperidine 1-ethyl-4-[4-[3-(1-piperidinyl)propyl]phenylmethyl]piperidine 1-ethyl-4-[4- [3-(hexamethyleneimin-1-yl)propyl]phenylmethyl]piperidine 1
-ethyl-4-[4-[3-(3-thiazolidinyl)propyl]phenylmethyl]piperidine 1-ethyl-4-[4-[3-(4-methyl-1-piperazinyl)propyl]phenylmethyl]piperidine 1- Ethyl-4-[4-[3-(4-phenyl-1-piperazinyl)propyl]phenylmethyl]piperidine 1
-ethyl-4-[4-(3-morpholinopropyl)phenylmethyl]piperidine

1-Ethyl-4-[4-[4-(N,N-
dimethylamino)butyl]phenylmethyl]piperidine 1-ethyl-4-[4-[4-(N,N-diethylamino)butyl]phenylmethyl]piperidine 1-ethyl-4-[4-[4-(N,N -dipropylamino)butyl]phenylmethyl]piperidine 1-ethyl-4-[4-[4-(N,N-dibutylamino)butyl]phenylmethyl]piperidine 1-ethyl-4-[4-[4-( N,N-diisopropylamino)butyl]phenylmethyl]piperidine 1-ethyl-4-[4-[4-(N,N-diisobutylamino)butyl]phenylmethyl]piperidine 1-ethyl-4
-[4-[4-(N,N-di-sec-butylamino)
Butyl]phenylmethyl]piperidine 1-ethyl-4-
[4-[4-(N,N-dipentylamino)butyl]phenylmethyl]piperidine 1-ethyl-4-[4-[4
-(1-pyrrolidinyl)butyl]phenylmethyl]piperidine 1-ethyl-4-[4-[4-(1-piperidinyl)butyl]phenylmethyl]piperidine 1-ethyl-4-[4-[4-(hexamethylene) imin-1-yl)butyl]phenylmethyl]piperidine 1-
Ethyl-4-[4-[4-(3-thiazolidinyl)butyl]phenylmethyl]piperidine 1-ethyl-4-[4-[4-(4-methyl-1-piperazinyl)butyl]phenylmethyl]piperidine 1- Ethyl-4-[4-[4-(4-phenyl-1-piperazinyl)butyl]phenylmethyl]piperidine 1-ethyl-4-[4-(4-morpholinobutyl)phenylmethyl]piperidine

1-Ethyl-4-[4-[5-(N,N-
dimethylamino)pentyl]phenylmethyl]piperidine 1-ethyl-4-[4-[5-(N,N-diethylamino)pentyl]phenylmethyl]piperidine 1-ethyl-4-[4-[5-(N,N -dipropylamino)pentyl]phenylmethyl]piperidine 1-ethyl-4-
[4-[5-(N,N-dibutylamino)pentyl]phenylmethyl]piperidine 1-ethyl-4-[4-[5
-(N,N-diisopropylamino)pentyl]phenylmethyl]piperidine 1-ethyl-4-[4-[5-(
N,N-diisobutylamino)pentyl]phenylmethyl]piperidine 1-ethyl-4-[4-[5-(N,N
-di-sec-butylamino)pentyl]phenylmethyl]piperidine 1-ethyl-4-[4-[5-(N,N
-dipentylamino)pentyl]phenylmethyl]piperidine 1-ethyl-4-[4-[5-(1-pyrrolidinyl)pentyl]phenylmethyl]piperidine 1-ethyl-4-[4-[5-(1-piperidinyl)] pentyl]phenylmethyl]piperidine 1-ethyl-4-[4-[5-(hexamethyleneimin-1-yl)pentyl]phenylmethyl]piperidine 1
-ethyl-4-[4-[5-(3-thiazolidinyl)pentyl]phenylmethyl]piperidine 1-ethyl-4-[4-[5-(4-methyl-1-piperazinyl)pentyl]phenylmethyl]piperidine 1 −
Ethyl-4-[4-[5-(4-phenyl-1-piperazinyl)pentyl]phenylmethyl]piperidine 1-ethyl-4-[4-(5-morpholinopentyl)phenylmethyl]piperidine

1-Propyl-4-[4-(N,N-dimethylaminomethyl)phenylmethyl]piperidine 1-propyl-4-[4-(N,N-diethylaminomethyl)
phenylmethyl]piperidine 1-propyl-4-[4-(N,N-dipropylaminomethyl)phenylmethyl]piperidine 1-propyl-4-[4-(N,N-dibutylaminomethyl)phenylmethyl]piperidine 1 -Propyl-4-[4-(N,N-diisopropylaminomethyl)phenylmethyl]piperidine 1-propyl-4-[4-(N,N-diisobutylaminomethyl)phenylmethyl]piperidine 1-propyl-4-[ 4-(N,N-di-sec-butylaminomethyl)phenylmethyl]piperidine 1-propyl-4-[4-(N,N-dipentylaminomethyl)
phenylmethyl]piperidine 1-propyl-4-[4-(1-pyrrolidinylmethyl)
phenylmethyl]piperidine 1-propyl-4-[4-(1-piperidinylmethyl)
phenylmethyl]piperidine 1-propyl-4-[4-(hexamethyleneimine-1
-ylmethyl)phenylmethyl]piperidine 1-propyl-4-[4-(3-thiazolidinylmethyl)phenylmethyl]piperidine 1-propyl-4-[4-(4-methyl-1-piperazinylmethyl)phenyl methyl]piperidine 1-propyl-4-[4-(4-phenyl-1-piperazinylmethyl)phenylmethyl]piperidine 1-propyl-4-[4
-(morpholinomethyl)phenylmethyl]piperidine

1-Propyl-4-[4-[2-(N,N
-dimethylamino)ethyl]phenylmethyl]piperidine 1-propyl-4-[4-[2-(N,N-diethylamino)ethyl]phenylmethyl]piperidine 1-propyl-4-[4-[2-(N, N-dipropylamino)
ethyl]phenylmethyl]piperidine 1-propyl-4
-[4-[2-(N,N-dibutylamino)ethyl]phenylmethyl]piperidine 1-propyl-4-[4-[
2-(N,N-diisopropylamino)ethyl]phenylmethyl]piperidine 1-propyl-4-[4-[2-
(N,N-diisobutylamino)ethyl]phenylmethyl]piperidine 1-propyl-4-[4-[2-(N,
N-di-sec-butylamino)ethyl]phenylmethyl]piperidine 1-propyl-4-[4-[2-(N,
N-dipentylamino)ethyl]phenylmethyl]piperidine 1-propyl-4-[4-[2-(1-pyrrolidinyl)ethyl]phenylmethyl]piperidine 1-propyl-4-[4-[2-(1-piperidinyl) )ethyl]phenylmethyl]piperidine 1-propyl-4-[4-[2-(hexamethyleneimine-1-
yl)ethyl]phenylmethyl]piperidine 1-propyl-4-[4-[2-(3-thiazolidinyl)ethyl]
phenylmethyl]piperidine 1-propyl-4-[4-[2-(4-methyl-1-piperazinyl)ethyl]phenylmethyl]piperidine 1-
Propyl-4-[4-[2-(4-phenyl-1-piperazinyl)ethyl]phenylmethyl]piperidine 1-propyl-4-[4-(2-morpholinoethyl)phenylmethyl]piperidine

1-Propyl-4-[4-[3-(N,N
-dimethylamino)propyl]phenylmethyl]piperidine 1-propyl-4-[4-[3-(N,N-diethylamino)propyl]phenylmethyl]piperidine 1-
Propyl-4-[4-[3-(N,N-dipropylamino)propyl]phenylmethyl]piperidine 1-propyl-4-[4-[3-(N,N-dibutylamino)propyl]phenylmethyl] Piperidine 1-propyl-4-
[4-[3-(N,N-diisopropylamino)propyl]phenylmethyl]piperidine 1-propyl-4-[
4-[3-(N,N-diisobutylamino)propyl]
phenylmethyl]piperidine 1-propyl-4-[4-
[3-(N,N-di-sec-butylamino)propyl]phenylmethyl]piperidine 1-propyl-4-[4
-[3-(N,N-dipentylamino)propyl]phenylmethyl]piperidine 1-propyl-4-[4-[3
-(1-pyrrolidinyl)propyl]phenylmethyl]piperidine 1-propyl-4-[4-[3-(1-piperidinyl)
propyl]phenylmethyl]piperidine 1-propyl-4-[4-[3-(hexamethyleneimin-1-yl)propyl]phenylmethyl]piperidine 1-propyl-4-[4-[3-(3-thiazolidinyl) propyl]phenylmethyl]piperidine 1-propyl-4-[4-[3-(4-methyl-1-piperazinyl)propyl]phenylmethyl]piperidine 1
-Propyl-4-[4-[3-(4-phenyl-1-piperazinyl)propyl]phenylmethyl]piperidine 1
-Propyl-4-[4-(3-morpholinopropyl)phenylmethyl]piperidine

1-Propyl-4-[4-[4-(N,N
-dimethylamino)butyl]phenylmethyl]piperidine 1-propyl-4-[4-[4-(N,N-diethylamino)butyl]phenylmethyl]piperidine 1-propyl-4-[4-[4-(N, N-dipropylamino)
Butyl]phenylmethyl]piperidine 1-propyl-4
-[4-[4-(N,N-dibutylamino)butyl]phenylmethyl]piperidine 1-propyl-4-[4-[
4-(N,N-diisopropylamino)butyl]phenylmethyl]piperidine 1-propyl-4-[4-[4-
(N,N-diisobutylamino)butyl]phenylmethyl]piperidine 1-propyl-4-[4-[4-(N,
N-di-sec-butylamino)butyl]phenylmethyl]piperidine 1-propyl-4-[4-[4-(N,
N-dipentylamino)butyl]phenylmethyl]piperidine 1-propyl-4-[4-[4-(1-pyrrolidinyl)butyl]phenylmethyl]piperidine 1-propyl-4-[4-[4-(1-piperidinyl) )
Butyl]phenylmethyl]piperidine 1-propyl-4-[4-[4-(hexamethyleneimin-1-yl)butyl]phenylmethyl]piperidine 1
-propyl-4-[4-[4-(3-thiazolidinyl)
butyl]phenylmethyl]piperidine 1-propyl-4-[4-[4-(4-methyl-1-piperazinyl)butyl]phenylmethyl]piperidine 1-
Propyl-4-[4-[4-(4-phenyl-1-piperazinyl)butyl]phenylmethyl]piperidine 1-propyl-4-[4-(4-morpholinobutyl)phenylmethyl]piperidine

1-Propyl-4-[4-[5-(N,N
-dimethylamino)pentyl]phenylmethyl]piperidine 1-propyl-4-[4-[5-(N,N-diethylamino)pentyl]phenylmethyl]piperidine 1-
Propyl-4-[4-[5-(N,N-dipropylamino)pentyl]phenylmethyl]piperidine 1-propyl-4-[4-[5-(N,N-dibutylamino)pentyl]phenylmethyl] Piperidine 1-propyl-4-
[4-[5-(N,N-diisopropylamino)pentyl]phenylmethyl]piperidine 1-propyl-4-[
4-[5-(N,N-diisobutylamino)pentyl]
phenylmethyl]piperidine 1-propyl-4-[4-
[5-(N,N-di-sec-butylamino)pentyl]phenylmethyl]piperidine 1-propyl-4-[4
-[5-(N,N-dipentylamino)pentyl]phenylmethyl]piperidine 1-propyl-4-[4-[5
-(1-pyrrolidinyl)pentyl]phenylmethyl]piperidine 1-propyl-4-[4-[5-(1-piperidinyl)
pentyl]phenylmethyl]piperidine 1-propyl-4-[4-[5-(hexamethyleneimin-1-yl)pentyl]phenylmethyl]piperidine 1-propyl-4-[4-[5-(3-thiazolidinyl) pentyl]phenylmethyl]piperidine 1-propyl-4-[4-[5-(4-methyl-1-piperazinyl)pentyl]phenylmethyl]piperidine 1
-Propyl-4-[4-[5-(4-phenyl-1-piperazinyl)pentyl]phenylmethyl]piperidine 1
-Propyl-4-[4-(5-morpholinopentyl)phenylmethyl]piperidine

1-Butyl-4-[4-(N,N-dimethylaminomethyl)phenylmethyl]piperidine 1-butyl-4-[4-(N,N-diethylaminomethyl)phenylmethyl]piperidine 1-butyl- 4-[4-(N,N-dipropylaminomethyl)phenylmethyl]piperidine 1-butyl-4-[4-(N,N-dibutylaminomethyl)phenylmethyl]piperidine 1-butyl-4-[4- (N,N-diisopropylaminomethyl)phenylmethyl]piperidine 1-butyl-4-[4-(N,N-diisobutylaminomethyl)phenylmethyl]piperidine 1-butyl-4-[4-(N,N-diisobutylaminomethyl)phenylmethyl] -sec-butylaminomethyl)phenylmethyl]piperidine 1-butyl-4-[4-(N,N-dipentylaminomethyl)phenylmethyl]piperidine 1-butyl-4-[4-(1-pyrrolidinylmethyl) phenylmethyl]piperidine 1-butyl-4-[4-(1-piperidinylmethyl)phenylmethyl]piperidine 1-butyl-4-[4-(hexamethyleneimine-1-
ylmethyl)phenylmethyl]piperidine 1-butyl-
4-[4-(3-thiazolidinylmethyl)phenylmethyl]piperidine 1-butyl-4-[4-(4-methyl-1-piperazinylmethyl)phenylmethyl]piperidine 1-butyl-4-[ 4-(4-phenyl-1-piperazinylmethyl)phenylmethyl]piperidine 1-butyl-
4-[4-(morpholinomethyl)phenylmethyl]piperidine

1-Butyl-4-[4-[2-(N,N-
dimethylamino)ethyl]phenylmethyl]piperidine 1-butyl-4-[4-[2-(N,N-diethylamino)ethyl]phenylmethyl]piperidine 1-butyl-4-[4-[2-(N,N -dipropylamino)ethyl]phenylmethyl]piperidine 1-butyl-4-[4-[2-(N,N-dibutylamino)ethyl]phenylmethyl]piperidine 1-butyl-4-[4-[2-( N,N-diisopropylamino)ethyl]phenylmethyl]piperidine 1-butyl-4-[4-[2-(N,N-diisobutylamino)ethyl]phenylmethyl]piperidine 1-butyl-4
-[4-[2-(N,N-di-sec-butylamino)
ethyl]phenylmethyl]piperidine 1-butyl-4-
[4-[2-(N,N-dipentylamino)ethyl]phenylmethyl]piperidine 1-butyl-4-[4-[2
-(1-pyrrolidinyl)ethyl]phenylmethyl]piperidine 1-butyl-4-[4-[2-(1-piperidinyl)ethyl]phenylmethyl]piperidine 1-butyl-4-[4-[2-(hexamethylene) imin-1-yl)ethyl]phenylmethyl]piperidine 1-
Butyl-4-[4-[2-(3-thiazolidinyl)ethyl]phenylmethyl]piperidine 1-Butyl-4-[4-[2-(4-methyl-1-piperazinyl)ethyl]phenylmethyl]piperidine 1- Butyl-4-[4-[2-(4-phenyl-1-piperazinyl)ethyl]phenylmethyl]piperidine 1-Butyl-4-[4-(2-morpholinoethyl)phenylmethyl]piperidine

1-Butyl-4-[4-[3-(N,N-
dimethylamino)propyl]phenylmethyl]piperidine 1-butyl-4-[4-[3-(N,N-diethylamino)propyl]phenylmethyl]piperidine 1-butyl-4-[4-[3-(N,N -dipropylamino)propyl]phenylmethyl]piperidine 1-butyl-4-
[4-[3-(N,N-dibutylamino)propyl]phenylmethyl]piperidine 1-butyl-4-[4-[3
-(N,N-diisopropylamino)propyl]phenylmethyl]piperidine 1-butyl-4-[4-[3-(
N,N-diisobutylamino)propyl]phenylmethyl]piperidine 1-butyl-4-[4-[3-(N,N
-di-sec-butylamino)propyl]phenylmethyl]piperidine 1-butyl-4-[4-[3-(N,N
-dipentylamino)propyl]phenylmethyl]piperidine 1-butyl-4-[4-[3-(1-pyrrolidinyl)propyl]phenylmethyl]piperidine 1-butyl-4-[4-[3-(1-piperidinyl)] propyl]phenylmethyl]piperidine 1-butyl-4-[4-[3-(hexamethyleneimin-1-yl)propyl]phenylmethyl]piperidine 1
-Butyl-4-[4-[3-(3-thiazolidinyl)propyl]phenylmethyl]piperidine 1-Butyl-4-[4-[3-(4-methyl-1-piperazinyl)propyl]phenylmethyl]piperidine 1 −
Butyl-4-[4-[3-(4-phenyl-1-piperazinyl)propyl]phenylmethyl]piperidine 1-butyl-4-[4-(3-morpholinopropyl)phenylmethyl]piperidine

1-Butyl-4-[4-[4-(N,N-
dimethylamino)butyl]phenylmethyl]piperidine 1-butyl-4-[4-[4-(N,N-diethylamino)butyl]phenylmethyl]piperidine 1-butyl-4-[4-[4-(N,N -dipropylamino)butyl]phenylmethyl]piperidine 1-butyl-4-[4-[4-(N,N-dibutylamino)butyl]phenylmethyl]piperidine 1-butyl-4-[4-[4-( N,N-diisopropylamino)butyl]phenylmethyl]piperidine 1-butyl-4-[4-[4-(N,N-diisobutylamino)butyl]phenylmethyl]piperidine 1-butyl-4
-[4-[4-(N,N-di-sec-butylamino)
butyl]phenylmethyl]piperidine 1-butyl-4-
[4-[4-(N,N-dipentylamino)butyl]phenylmethyl]piperidine 1-butyl-4-[4-[4
-(1-pyrrolidinyl)butyl]phenylmethyl]piperidine 1-butyl-4-[4-[4-(1-piperidinyl)butyl]phenylmethyl]piperidine 1-butyl-4-[4-[4-(hexamethylene) imin-1-yl)butyl]phenylmethyl]piperidine 1-
Butyl-4-[4-[4-(3-thiazolidinyl)butyl]phenylmethyl]piperidine 1-butyl-4-[4-[4-(4-methyl-1-piperazinyl)butyl]phenylmethyl]piperidine 1- Butyl-4-[4-[4-(4-phenyl-1-piperazinyl)butyl]phenylmethyl]piperidine 1-butyl-4-[4-(4-morpholinobutyl)phenylmethyl]piperidine

1-Butyl-4-[4-[5-(N,N-
dimethylamino)pentyl]phenylmethyl]piperidine 1-butyl-4-[4-[5-(N,N-diethylamino)pentyl]phenylmethyl]piperidine 1-butyl-4-[4-[5-(N,N -dipropylamino)pentyl]phenylmethyl]piperidine 1-butyl-4-
[4-[5-(N,N-dibutylamino)pentyl]phenylmethyl]piperidine 1-butyl-4-[4-[5
-(N,N-diisopropylamino)pentyl]phenylmethyl]piperidine 1-butyl-4-[4-[5-(
N,N-diisobutylamino)pentyl]phenylmethyl]piperidine 1-butyl-4-[4-[5-(N,N
-di-sec-butylamino)pentyl]phenylmethyl]piperidine 1-butyl-4-[4-[5-(N,N
-dipentylamino)pentyl]phenylmethyl]piperidine 1-butyl-4-[4-[5-(1-pyrrolidinyl)pentyl]phenylmethyl]piperidine 1-butyl-4-[4-[5-(1-piperidinyl)] pentyl]phenylmethyl]piperidine 1-butyl-4-[4-[5-(hexamethyleneimin-1-yl)pentyl]phenylmethyl]piperidine 1
-Butyl-4-[4-[5-(3-thiazolidinyl)pentyl]phenylmethyl]piperidine 1-Butyl-4-[4-[5-(4-methyl-1-piperazinyl)pentyl]phenylmethyl]piperidine 1 −
Butyl-4-[4-[5-(4-phenyl-1-piperazinyl)pentyl]phenylmethyl]piperidine 1-Butyl-4-[4-(5-morpholinopentyl)phenylmethyl]piperidine

1-pentyl-4-[4-(N,N-dimethylaminomethyl)phenylmethyl]piperidine 1-pentyl-4-[4-(N,N-diethylaminomethyl)
phenylmethyl]piperidine 1-pentyl-4-[4-(N,N-dipropylaminomethyl)phenylmethyl]piperidine 1-pentyl-4-[4-(N,N-dibutylaminomethyl)phenylmethyl]piperidine 1 -Pentyl-4-[4-(N,N-diisopropylaminomethyl)phenylmethyl]piperidine 1-pentyl-4-[4-(N,N-diisobutylaminomethyl)phenylmethyl]piperidine 1-pentyl-4-[ 4-(N,N-di-sec-butylaminomethyl)phenylmethyl]piperidine 1-pentyl-4-[4-(N,N-dipentylaminomethyl)
phenylmethyl]piperidine 1-pentyl-4-[4-(1-pyrrolidinylmethyl)
phenylmethyl]piperidine 1-pentyl-4-[4-(1-piperidinylmethyl)
phenylmethyl]piperidine 1-pentyl-4-[4-(hexamethyleneimine-1
-ylmethyl)phenylmethyl]piperidine 1-pentyl-4-[4-(3-thiazolidinylmethyl)phenylmethyl]piperidine 1-pentyl-4-[4-(4-methyl-1-piperazinylmethyl) phenylmethyl]piperidine 1-pentyl-4-[4-(4-phenyl-1-piperazinylmethyl)phenylmethyl]piperidine 1-pentyl-4-[4
-(morpholinomethyl)phenylmethyl]piperidine

1-Pentyl-4-[4-[2-(N,N
-dimethylamino)ethyl]phenylmethyl]piperidine 1-pentyl-4-[4-[2-(N,N-diethylamino)ethyl]phenylmethyl]piperidine 1-pentyl-4-[4-[2-(N, N-dipropylamino)
ethyl]phenylmethyl]piperidine 1-pentyl-4
-[4-[2-(N,N-dibutylamino)ethyl]phenylmethyl]piperidine 1-pentyl-4-[4-[
2-(N,N-diisopropylamino)ethyl]phenylmethyl]piperidine 1-pentyl-4-[4-[2-
(N,N-diisobutylamino)ethyl]phenylmethyl]piperidine 1-pentyl-4-[4-[2-(N,
N-di-sec-butylamino)ethyl]phenylmethyl]piperidine 1-pentyl-4-[4-[2-(N,
N-dipentylamino)ethyl]phenylmethyl]piperidine 1-pentyl-4-[4-[2-(1-pyrrolidinyl)ethyl]phenylmethyl]piperidine 1-pentyl-4-[4-[2-(1-piperidinyl) )
ethyl]phenylmethyl]piperidine 1-pentyl-4-[4-[2-(hexamethyleneimin-1-yl)ethyl]phenylmethyl]piperidine 1
-pentyl-4-[4-[2-(3-thiazolidinyl)
ethyl]phenylmethyl]piperidine 1-pentyl-4-[4-[2-(4-methyl-1-piperazinyl)ethyl]phenylmethyl]piperidine 1-
Pentyl-4-[4-[2-(4-phenyl-1-piperazinyl)ethyl]phenylmethyl]piperidine 1-pentyl-4-[4-(2-morpholinoethyl)phenylmethyl]piperidine

1-pentyl-4-[4-[3-(N,N
-dimethylamino)propyl]phenylmethyl]piperidine 1-pentyl-4-[4-[3-(N,N-diethylamino)propyl]phenylmethyl]piperidine 1-
Pentyl-4-[4-[3-(N,N-dipropylamino)propyl]phenylmethyl]piperidine 1-pentyl-4-[4-[3-(N,N-dibutylamino)propyl]phenylmethyl] piperidine 1-pentyl-4-
[4-[3-(N,N-diisopropylamino)propyl]phenylmethyl]piperidine 1-pentyl-4-[
4-[3-(N,N-diisobutylamino)propyl]
phenylmethyl]piperidine 1-pentyl-4-[4-
[3-(N,N-di-sec-butylamino)propyl]phenylmethyl]piperidine 1-pentyl-4-[4
-[3-(N,N-dipentylamino)propyl]phenylmethyl]piperidine 1-pentyl-4-[4-[3
-(1-pyrrolidinyl)propyl]phenylmethyl]piperidine 1-pentyl-4-[4-[3-(1-piperidinyl)
propyl]phenylmethyl]piperidine 1-pentyl-4-[4-[3-(hexamethyleneimin-1-yl)propyl]phenylmethyl]piperidine 1-pentyl-4-[4-[3-(3-thiazolidinyl) propyl]phenylmethyl]piperidine 1-pentyl-4-[4-[3-(4-methyl-1-piperazinyl)propyl]phenylmethyl]piperidine 1
-pentyl-4-[4-[3-(4-phenyl-1-piperazinyl)propyl]phenylmethyl]piperidine 1
-pentyl-4-[4-(3-morpholinopropyl)phenylmethyl]piperidine

1-pentyl-4-[4-[4-(N,N
-dimethylamino)butyl]phenylmethyl]piperidine 1-pentyl-4-[4-[4-(N,N-diethylamino)butyl]phenylmethyl]piperidine 1-pentyl-4-[4-[4-(N, N-dipropylamino)
Butyl]phenylmethyl]piperidine 1-pentyl-4
-[4-[4-(N,N-dibutylamino)butyl]phenylmethyl]piperidine 1-pentyl-4-[4-[
4-(N,N-diisopropylamino)butyl]phenylmethyl]piperidine 1-pentyl-4-[4-[4-
(N,N-diisobutylamino)butyl]phenylmethyl]piperidine 1-pentyl-4-[4-[4-(N,
N-di-sec-butylamino)butyl]phenylmethyl]piperidine 1-pentyl-4-[4-[4-(N,
N-dipentylamino)butyl]phenylmethyl]piperidine 1-pentyl-4-[4-[4-(1-pyrrolidinyl)butyl]phenylmethyl]piperidine 1-pentyl-4-[4-[4-(1-piperidinyl) )
butyl]phenylmethyl]piperidine 1-pentyl-4-[4-[4-(hexamethyleneimin-1-yl)butyl]phenylmethyl]piperidine 1
-pentyl-4-[4-[4-(3-thiazolidinyl)
butyl]phenylmethyl]piperidine 1-pentyl-4-[4-[4-(4-methyl-1-piperazinyl)butyl]phenylmethyl]piperidine 1-
Pentyl-4-[4-[4-(4-phenyl-1-piperazinyl)butyl]phenylmethyl]piperidine 1-pentyl-4-[4-(4-morpholinobutyl)phenylmethyl]piperidine

1-pentyl-4-[4-[5-(N,N
-dimethylamino)pentyl]phenylmethyl]piperidine 1-pentyl-4-[4-[5-(N,N-diethylamino)pentyl]phenylmethyl]piperidine 1-
Pentyl-4-[4-[5-(N,N-dipropylamino)pentyl]phenylmethyl]piperidine 1-pentyl-4-[4-[5-(N,N-dibutylamino)pentyl]phenylmethyl] piperidine 1-pentyl-4-
[4-[5-(N,N-diisopropylamino)pentyl]phenylmethyl]piperidine 1-pentyl-4-[
4-[5-(N,N-diisobutylamino)pentyl]
phenylmethyl]piperidine 1-pentyl-4-[4-
[5-(N,N-di-sec-butylamino)pentyl]phenylmethyl]piperidine 1-pentyl-4-[4
-[5-(N,N-dipentylamino)pentyl]phenylmethyl]piperidine 1-pentyl-4-[4-[5
-(1-pyrrolidinyl)pentyl]phenylmethyl]piperidine 1-pentyl-4-[4-[5-(1-piperidinyl)
pentyl]phenylmethyl]piperidine 1-pentyl-4-[4-[5-(hexamethyleneimin-1-yl)pentyl]phenylmethyl]piperidine 1-pentyl-4-[4-[5-(3-thiazolidinyl) pentyl]phenylmethyl]piperidine 1-pentyl-4-[4-[5-(4-methyl-1-piperazinyl)pentyl]phenylmethyl]piperidine 1
-pentyl-4-[4-[5-(4-phenyl-1-piperazinyl)pentyl]phenylmethyl]piperidine 1
-pentyl-4-[4-(5-morpholinopentyl)phenylmethyl]piperidine

1-Phenylmethyl-4-[4-(N,N
-dimethylaminomethyl)phenylmethyl]piperidine 1-phenylmethyl-4-[4-(N,N-diethylaminomethyl)phenylmethyl]piperidine 1-phenylmethyl-4-[4-(N,N-dipropylaminomethyl) ) phenylmethyl]piperidine 1-phenylmethyl-4
-[4-(N,N-dibutylaminomethyl)phenylmethyl]piperidine 1-phenylmethyl-4-[4-(N
, N-diisopropylaminomethyl)phenylmethyl]
piperidine 1-phenylmethyl-4-[4-(N,N-
diisobutylaminomethyl)phenylmethyl]piperidine 1-phenylmethyl-4-[4-(N,N-di-se
c-butylaminomethyl)phenylmethyl]piperidine 1-phenylmethyl-4-[4-(N,N-dipentylaminomethyl)phenylmethyl]piperidine 1-phenylmethyl-4-[4-(1-pyrrolidinylmethyl) ) phenylmethyl]piperidine 1-phenylmethyl-4-[4-(1-piperidinylmethyl)phenylmethyl]piperidine 1-phenylmethyl-4-[4-(hexamethyleneimin-1-ylmethyl)phenylmethyl]piperidine 1-
Phenylmethyl-4-[4-(3-thiazolidinylmethyl)phenylmethyl]piperidine 1-phenylmethyl-4-[4-(4-methyl-1-piperazinylmethyl)phenylmethyl]piperidine 1-phenyl Methyl-4-[4-(4-phenyl-1-piperazinylmethyl)phenylmethyl]piperidine 1-phenylmethyl-4-[4-(morpholinomethyl)phenylmethyl]piperidine

1-phenylmethyl-4-[4-[2-(
N,N-dimethylamino)ethyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[2-(N,N-diethylamino)ethyl]phenylmethyl]piperidine 1-
Phenylmethyl-4-[4-[2-(N,N-dipropylamino)ethyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[2-(N,N-dibutylamino)ethyl]phenyl methyl]piperidine 1-phenylmethyl-4-[4-[2-(N,N-diisopropylamino)ethyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[2-(N,N-diisobutylamino) )ethyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[2-(N,N-di-sec-
butylamino)ethyl]phenylmethyl]piperidine 1
-Phenylmethyl-4-[4-[2-(N,N-dipentylamino)ethyl]phenylmethyl]piperidine 1-
Phenylmethyl-4-[4-[2-(1-pyrrolidinyl)ethyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[2-(1-piperidinyl)ethyl]
phenylmethyl]piperidine 1-phenylmethyl-4-
[4-[2-(hexamethyleneimin-1-yl)ethyl]phenylmethyl]piperidine 1-phenylmethyl-
4-[4-[2-(3-thiazolidinyl)ethyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4
-[2-(4-Methyl-1-piperazinyl)ethyl]phenylmethyl]piperidine 1-phenylmethyl-4-[
4-[2-(4-phenyl-1-piperazinyl)ethyl]phenylmethyl]piperidine 1-phenylmethyl-4
-[4-(2-morpholinoethyl)phenylmethyl]piperidine

1-phenylmethyl-4-[4-[3-(
N,N-dimethylamino)propyl]phenylmethyl]
Piperidine 1-phenylmethyl-4-[4-[3-(N,N-diethylamino)propyl]phenylmethyl]piperidine 1
-Phenylmethyl-4-[4-[3-(N,N-dipropylamino)propyl]phenylmethyl]piperidine 1
-Phenylmethyl-4-[4-[3-(N,N-dibutylamino)propyl]phenylmethyl]piperidine 1-
Phenylmethyl-4-[4-[3-(N,N-diisopropylamino)propyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[3-(N,N-diisobutylamino)propyl]phenylmethyl ] Piperidine 1-phenylmethyl-4-[4-[3-(N,N-di-sec-butylamino)propyl]phenylmethyl]
piperidine 1-phenylmethyl-4-[4-[3-(N
,N-dipentylamino)propyl]phenylmethyl]
piperidine 1-phenylmethyl-4-[4-[3-(1
-pyrrolidinyl)propyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[3-(1-piperidinyl)propyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[3-(hexamethyleneimine) -1-yl)propyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[3-(3-thiazolidinyl)propyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[3-(4 -Methyl-1-piperazinyl)propyl]phenylmethyl]piperidine 1
-phenylmethyl-4-[4-[3-(4-phenyl-
1-Piperazinyl)propyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-(3-morpholinopropyl)phenylmethyl]piperidine

1-Phenylmethyl-4-[4-[4-(
N,N-dimethylamino)butyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[4-(N,N-diethylamino)butyl]phenylmethyl]piperidine 1-
Phenylmethyl-4-[4-[4-(N,N-dipropylamino)butyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[4-(N,N-dibutylamino)butyl]phenyl methyl]piperidine 1-phenylmethyl-4-[4-[4-(N,N-diisopropylamino)butyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[4-(N,N-diisobutylamino) )butyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[4-(N,N-di-sec-
butylamino)butyl]phenylmethyl]piperidine 1
-Phenylmethyl-4-[4-[4-(N,N-dipentylamino)butyl]phenylmethyl]piperidine 1-
Phenylmethyl-4-[4-[4-(1-pyrrolidinyl)butyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[4-(1-piperidinyl)butyl]
phenylmethyl]piperidine 1-phenylmethyl-4-
[4-[4-(hexamethyleneimin-1-yl)butyl]phenylmethyl]piperidine 1-phenylmethyl-
4-[4-[4-(3-thiazolidinyl)butyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4
-[4-(4-Methyl-1-piperazinyl)butyl]phenylmethyl]piperidine 1-phenylmethyl-4-[
4-[4-(4-phenyl-1-piperazinyl)butyl]phenylmethyl]piperidine 1-phenylmethyl-4
-[4-(4-morpholinobutyl)phenylmethyl]piperidine

1-Phenylmethyl-4-[4-[5-(
N,N-dimethylamino)pentyl]phenylmethyl]
Piperidine 1-phenylmethyl-4-[4-[5-(N,N-diethylamino)pentyl]phenylmethyl]piperidine 1
-Phenylmethyl-4-[4-[5-(N,N-dipropylamino)pentyl]phenylmethyl]piperidine 1
-Phenylmethyl-4-[4-[5-(N,N-dibutylamino)pentyl]phenylmethyl]piperidine 1-
Phenylmethyl-4-[4-[5-(N,N-diisobutylamino)pentyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[5-(N,N-diisobutylamino)pentyl]phenylmethyl ]Piperidine 1-phenylmethyl-4-[4-[5-(N,N-di-sec-butylamino)pentyl]phenylmethyl]
piperidine 1-phenylmethyl-4-[4-[5-(N
,N-dipentylamino)pentyl]phenylmethyl]
piperidine 1-phenylmethyl-4-[4-[5-(1
-pyrrolidinyl)pentyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[5-(1-piperidinyl)pentyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[5-(hexamethyleneimine) -1-yl)pentyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[5-(3-thiazolidinyl)pentyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-[5-(4 -Methyl-1-piperazinyl)pentyl]phenylmethyl]piperidine 1
-phenylmethyl-4-[4-[5-(4-phenyl-
1-Piperazinyl)pentyl]phenylmethyl]piperidine 1-phenylmethyl-4-[4-(5-morpholinopentyl)phenylmethyl]piperidine

1-diphenylmethyl-4-[4-(N,
N-dimethylaminomethyl)phenylmethyl]piperidine 1-diphenylmethyl-4-[4-(N,N-diethylaminomethyl)phenylmethyl]piperidine 1-diphenylmethyl-4-[4-(N,N-dipropylamino) methyl)phenylmethyl]piperidine 1-diphenylmethyl-4-[4-(N,N-dibutylaminomethyl)phenylmethyl]piperidine 1-diphenylmethyl-4-
[4-(N,N-diisopropylaminomethyl)phenylmethyl]piperidine 1-diphenylmethyl-4-[4
-(N,N-diisobutylaminomethyl)phenylmethyl]piperidine 1-diphenylmethyl-4-[4-(N
, N-di-sec-butylaminomethyl)phenylmethyl]piperidine 1-diphenylmethyl-4-[4-(N
,N-dipentylaminomethyl)phenylmethyl]piperidine 1-diphenylmethyl-4-[4-(1-pyrrolidinylmethyl)phenylmethyl]piperidine 1-diphenylmethyl-4-[4-(1-piperidinylmethyl) ) phenylmethyl]piperidine 1-diphenylmethyl-4-[4-(hexamethyleneimin-1-ylmethyl)phenylmethyl]piperidine 1
-diphenylmethyl-4-[4-(3-thiazolidinylmethyl)phenylmethyl]piperidine 1-diphenylmethyl-4-[4-(4-methyl-1-
Piperazinylmethyl)phenylmethyl]piperidine 1-
Diphenylmethyl-4-[4-(4-phenyl-1-piperazinylmethyl)phenylmethyl]piperidine 1-diphenylmethyl-4-[4-(morpholinomethyl)phenylmethyl]piperidine

1-diphenylmethyl-4-[4-[2-
(N,N-dimethylamino)ethyl]phenylmethyl]
Piperidine 1-diphenylmethyl-4-[4-[2-(N,N-diethylamino)ethyl]phenylmethyl]piperidine 1
-diphenylmethyl-4-[4-[2-(N,N-dipropylamino)ethyl]phenylmethyl]piperidine 1
-diphenylmethyl-4-[4-[2-(N,N-dibutylamino)ethyl]phenylmethyl]piperidine 1-
Diphenylmethyl-4-[4-[2-(N,N-diisopropylamino)ethyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[2-(N,N-diisobutylamino)ethyl]phenylmethyl ]piperidine 1-diphenylmethyl-4-[4-[2-(N,N-
di-sec-butylamino)ethyl]phenylmethyl]
piperidine 1-diphenylmethyl-4-[4-[2-(
N,N-dipentylamino)ethyl]phenylmethyl]
piperidine 1-diphenylmethyl-4-[4-[2-(
1-pyrrolidinyl)ethyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[2-(1-piperidinyl)ethyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[2-(hexamethylene) imin-1-yl)ethyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[2-(3-thiazolidinyl)ethyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[2-( 4-methyl-1-
piperazinyl)ethyl]phenylmethyl]piperidine 1
-diphenylmethyl-4-[4-[2-(4-phenyl-1-piperazinyl)ethyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-(2-morpholinoethyl)phenylmethyl]piperidine

1-diphenylmethyl-4-[4-[3-
(N,N-dimethylamino)propyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[3-(N,N-diethylamino)propyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4- [3-(N,N-dipropylamino)propyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[3-(N,N-
dibutylamino)propyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[3-(N,N-
diisopropylamino)propyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[3-(N
, N-diisobutylamino)propyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[3-
(N,N-di-sec-butylamino)propyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[
4-[3-(N,N-dipentylamino)propyl]phenylmethyl]piperidine 1-diphenylmethyl-4-
[4-[3-(1-pyrrolidinyl)propyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-
[3-(1-piperidinyl)propyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[3-
(hexamethyleneimin-1-yl)propyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[3-(3-thiazolidinyl)propyl]phenylmethyl]piperidine 1-
diphenylmethyl-4-[4-[3-(4-methyl-1
-piperazinyl)propyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[3-(4-phenyl-1-piperazinyl)propyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-(3- Morpholinopropyl)phenylmethyl]piperidine

1-diphenylmethyl-4-[4-[4-
(N,N-dimethylamino)butyl]phenylmethyl]
Piperidine 1-diphenylmethyl-4-[4-[4-(N,N-diethylamino)butyl]phenylmethyl]piperidine 1
-diphenylmethyl-4-[4-[4-(N,N-dipropylamino)butyl]phenylmethyl]piperidine 1
-diphenylmethyl-4-[4-[4-(N,N-dibutylamino)butyl]phenylmethyl]piperidine 1-
Diphenylmethyl-4-[4-[4-(N,N-diisopropylamino)butyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[4-(N,N-diisobutylamino)butyl]phenylmethyl ] Piperidine 1-diphenylmethyl-4-[4-[4-(N,N-
di-sec-butylamino)butyl]phenylmethyl]
piperidine 1-diphenylmethyl-4-[4-[4-(
N,N-dipentylamino)butyl]phenylmethyl]
piperidine 1-diphenylmethyl-4-[4-[4-(
1-pyrrolidinyl)butyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[4-(1-piperidinyl)butyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[4-(hexamethylene) imin-1-yl)butyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[4-(3-thiazolidinyl)butyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[4-( 4-methyl-1-
piperazinyl)butyl]phenylmethyl]piperidine 1
-diphenylmethyl-4-[4-[4-(4-phenyl-1-piperazinyl)butyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-(4-morpholinobutyl)phenylmethyl]piperidine

1-diphenylmethyl-4-[4-[5-
(N,N-dimethylamino)pentyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[5-(N,N-diethylamino)pentyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4- [5-(N,N-dipropylamino)pentyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[5-(N,N-
dibutylamino)pentyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[5-(N,N-
diisopropylamino)pentyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[5-(N
, N-diisobutylamino)pentyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[5-
(N,N-di-sec-butylamino)pentyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[
4-[5-(N,N-dipentylamino)pentyl]phenylmethyl]piperidine 1-diphenylmethyl-4-
[4-[5-(1-pyrrolidinyl)pentyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-
[5-(1-piperidinyl)pentyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[5-
(hexamethyleneimin-1-yl)pentyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[5-(3-thiazolidinyl)pentyl]phenylmethyl]piperidine 1-
diphenylmethyl-4-[4-[5-(4-methyl-1
-piperazinyl)pentyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-[5-(4-phenyl-1-piperazinyl)pentyl]phenylmethyl]piperidine 1-diphenylmethyl-4-[4-(5- Morpholinopentyl)phenylmethyl]piperidine

4-[2-chloro-4-(N,N-dimethylaminomethyl)phenylmethyl]piperidine 4-[3
-chloro-4-(N,N-dimethylaminomethyl)phenylmethyl]piperidine 4-[2-methyl-4-(N,N-dimethylaminomethyl)phenylmethyl]piperidine 4-[3-methyl-4-( N,N-dimethylaminomethyl)phenylmethyl]piperidine 4-[2-methoxy-4-(N,N-dimethylaminomethyl)phenylmethyl]piperidine 4-[3-methoxy-4-(N,N-dimethylamino methyl)phenylmethyl]piperidine 4-[2-chloro-4-(N,N-diethylaminomethyl)phenylmethyl]piperidine 4-[3-chloro-4-(N,N-diethylaminomethyl)phenylmethyl]piperidine 4- [2-Methyl-4-(N,N-diethylaminomethyl)phenylmethyl]piperidine 4-[3-methyl-4-(N,N-diethylaminomethyl)phenylmethyl]piperidine 4-[2-methoxy-4-( N,N-diethylaminomethyl)phenylmethyl]piperidine 4-[3-methoxy-4-(N,N-diethylaminomethyl)phenylmethyl]piperidine

4-[2-chloro-4-[2-(N,N-
diethylamino)ethyl]phenylmethyl]piperidine 4-[3-chloro-4-[2-(N,N-diethylamino)ethyl]phenylmethyl]piperidine 4-[2-methyl-4-[2-(N,N- diethylamino)ethyl]
phenylmethyl]piperidine 4-[3-methyl-4-[
2-(N,N-diethylamino)ethyl]phenylmethyl]piperidine 4-[2-methoxy-4-[2-(N,
N-diethylamino)ethyl]phenylmethyl]piperidine 4-[3-methoxy-4-[2-(N,N-diethylamino)ethyl]phenylmethyl]piperidine

00
62 Compounds (Ia), (Ib), (Ic) and (I
The object of the present invention (I) or a salt thereof containing e), especially compound (Ic) or a salt thereof, can be used to treat various symptoms during the acute phase of stroke and aftereffects of stroke, intracerebral hypoxia, various symptoms associated with cerebral ischemia, and cerebral hypoxia. It has been shown to protect the brain and nerve cells against microcirculatory disorders, symptoms associated with head trauma, symptoms after surgery, especially cerebral edema, and disturbances of consciousness, making it safe for the prevention or treatment of these diseases. It can be used for. The compound (I) of the present invention or a salt thereof has low toxicity, and when used for the treatment of cerebral edema, acute stroke treatment, prevention and treatment of stroke sequelae, etc., it can be used in tablets, granules, capsules, etc. It can be administered orally or parenterally to mammals including humans in various dosage forms such as tablets, injections, and suppositories. The dosage varies depending on the type of disease and symptoms, etc.
Generally, in adults, when administered by injection, 0 per day
．． 1 mg to 3 g, preferably 0.3 mg to 30 mg, most preferably 3 mg to 50 mg. For oral administration, preferably 1 mg to 1 g, most preferably 10 mg to 300 mg per day.

[0063]

[Examples] Next, the present invention will be explained in more detail with reference to Examples, Formulation Examples, and Test Examples, but it goes without saying that the present invention is not limited thereto. Example 1

embedded image 4-[4-(N,N-dimethylaminocarbonyl)phenylmethyl]piperidine (1) Bromobenzene (65.4 g) and N-acetylisonipecotic acid chloride (79.2 g) were dissolved in dichloromethane ( 300 ml), anhydrous aluminum chloride (11
1 g) was gradually added. After stirring at room temperature for 2 hours, the solution was added to ice water, and the aqueous layer was further extracted with dichloromethane. Combine the dichloromethane layers and wash with water,
It was dried with anhydrous magnesium sulfate. After distilling off the solvent, the obtained solid was suspended in hexane and collected by filtration, with a melting point of 107-10
76 g of colorless solid 1-acetyl-4-(4-bromobenzoyl)piperidine was obtained at 8°C. (2) 1-acetyl-4-(4-bromobenzoyl)piperidine (76 g) was dissolved in dimethylformamide (20 g).
0 ml), and cuprous cyanide (43.9 g
) and heated under reflux for 5 hours. This solution was mixed with 1 N hydrochloric acid (500 m
After pouring into a solution dissolved in 1), the mixture was extracted with ethyl acetate (200 ml x 3), the organic layer was washed with water, and the solvent was distilled off. Add concentrated hydrochloric acid (500ml) to the remaining oily compound.
) and heated under reflux for 20 hours. The solvent was concentrated, dioxane (500 ml) was added thereto, and the precipitated solid was collected by filtration to obtain colorless crystals of 4-(4-hydroxycarbonylbenzoyl)piperidine monohydrochloride (46 g) with a melting point of 256-258°C. . (3) 4-(4-hydroxycarbonylbenzoyl)piperidine monohydrochloride (44.4 g) obtained above was dissolved in a mixed solvent of water (300 ml) and concentrated hydrochloric acid (30 ml), and 10% palladium/carbon was added as a catalyst. 70℃, 1
Catalytic hydrogen reduction was performed at atmospheric pressure. After absorbing 2 equivalents of hydrogen,
The catalyst was filtered off and solid sodium hydroxide (40 g) was slowly added to the mother liquor while cooling it with ice. Ditert-butyl carbonate (60 ml) was added dropwise to this solution at room temperature, and the mixture was further stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was made acidic with a 10% aqueous citric acid solution, and then extracted with ethyl acetate (300 ml x 3). After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was suspended in a small amount of ethyl ether.
Colorless solids 1-3 with a melting point of 166°C were collected by filtration.
Butyloxycarbonyl-4-[4-(hydroxycarbonyl)phenylmethyl]piperidine (43 g) was obtained. (4) 1-tert-butyloxycarbonyl-4-[4
To a solution of -(hydroxycarbonyl)phenylmethyl]piperidine (6.4 g) in dimethylformamide (50 ml) were added dimethylamine hydrochloride (2.44 g) and triethylamine (8.4 ml), and then diethyl cyanophosphate (4. 9 ml) was added thereto, and the mixture was stirred at room temperature for 2 hours. Water (10 ml) was added to the reaction solution, and the mixture was further stirred at room temperature for 1 hour, and then the reaction solution was made acidic with a 10% aqueous citric acid solution. After extraction with ethyl acetate (100 ml x 2), it was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained oily compound was purified by silica gel column chromatography (developing solvent: ethyl acetate) to obtain a colorless oily compound, 1-tert-butyloxycarbonyl-4-[4-(N, N-dimethylaminocarbonyl)
6.5 g of phenylmethyl]piperidine was obtained. NMR (CDCl3): δ=0.9-1.4 (2H,
m), 1.43 (9H, s), 1.4-1.9 (3H,
m), 2.56 (2H, d), 2.4-2.9 (2H,
m), 3.03 (6H, s), 3.9-4.3 (2H,
m), 7.05-7.40 (4H, m). (5) 1-tert-butyloxycarbonyl-4-[4
-(N,N-dimethylaminocarbonyl)phenylmethyl]piperidine (6.5 g) was added to trifluoroacetic acid (30
ml) and left at room temperature for 30 minutes. Trifluoroacetic acid was distilled off, 50 ml of water was added to the remaining oily compound, and the mixture was made basic with a 10% aqueous sodium hydroxide solution. After extraction with ethyl acetate, drying over anhydrous magnesium sulfate and distilling off the solvent, a colorless oily compound 4-
[4-(N,N-dimethylaminocarbonyl)phenylmethyl]piperidine (4.1 g) was obtained. NMR (CD
Cl3): δ=1.1-2.0 (5H, m). 2.6
2 (2H, d), 2.7-3.0 (2H, m), 3.0
3 (6H, s), 3.1-3.5 (2H, m), 7.1
~7.4 (4H, m).

Example 2

embedded image 4-[4-(N,N-dimethylaminomethyl)phenylmethyl]piperidine dihydrochloride 4-[4-(N,N-dimethylaminocarbonyl)phenylmethyl]piperidine (3.3 g) was anhydrous. Dissolved in tetrahydrofuran (50 ml), added lithium aluminum hydride (0.97 g) to it at room temperature, and then heated to 60°C.
It was heated for 2 hours. Return the reaction solution to room temperature and add water (
1.6 ml), 10% aqueous sodium hydroxide solution (1.2
ml), the precipitate was filtered off. After adding a 2N hydrogen chloride dioxane solution (20 ml) to the mother liquor, the solvent was distilled off and the residue was recrystallized from ethanol to obtain 2.1 g of colorless crystals with a melting point of 258-265°C. Elemental analysis value: Calculated value as C15H26Cl2N2:
C, 59.01; H, 8.58; N, 9.1
8 Actual measurement value: C, 59.13; H, 8.48; N
, 9.01NMR (D2O): δ=1.2-2.1
(5H, m), 2.70 (2H, d), 2.8-3.2
(2H, m), 2.78 (6H, s), 3.3-3.7
(2H, m), 4.33 (2H, s), 7.3-7.6
(4H, m).

Example 3

embedded image 4-[4-(N,N-diethylaminocarbonyl)phenylmethyl]piperidine (1) 1-tert-butyloxycarbonyl-4-[4-(hydroxycarbonyl)phenylmethyl obtained in Example 1 ] Using piperidine (6.4 g) and diethylamine hydrochloride (2.2 g), 1-
Tert-butyloxycarbonyl-4-[4-(N,N-diethylaminocarbonyl)phenylmethyl]piperidine (6.1 g) was obtained. NMR (CDCl3): δ=0.9-1.4 (2H,
m), 1.28 (6H, t), 1.47 (9H, s),
1.4-1.9 (3H, m), 2.56 (2H, d),
2.45-2.85 (2H, m), 3.43 (4H,
q), 3.9-4.3 (2H, m), 7.05-7.4
5 (4H, m). (2) 1-tert-butyloxycarbonyl-4-[4
A colorless oily compound 4-[4-
(N,N-diethylaminocarbonyl)phenylmethyl]piperidine (3.4 g) was obtained. NMR (CDCl3): δ=1.1-2.0 (5H,
m), 1.25 (6H, t), 2.65 (2H, d),
2.6-2.9 (2H, m), 3.1-3.5 (2H,
m), 3.40 (4H, q), 7.1 to 7.4 (4H,
m).

Example 4

embedded image 4-[4-(N,N-diethylaminomethyl)phenylmethyl]piperidine dihydrochloride 1-tert-butyloxycarbonyl-4-[4-(N,N
-diethylaminocarbonyl)phenylmethyl]piperidine (2.0 g) in the same manner as in Example 2,
1.4 g of colorless amorphous solid was obtained. Elemental analysis value: Calculated value as C17H30Cl2N2:
C, 61.25; H, 9.07; N, 8.4
0 actual measurement value: C, 61.47; H, 8.98; N
, 8.33NMR (D2O): δ=1.2-2.1
(5H, m), 1.32 (6H, t), 2.70 (2H
, d), 2.8-3.2 (2H, m), 3.22 (4H
, q), 3.3-3.7 (2H, m), 4.32 (2H
, s), 7.3-7.6 (4H, m).

Example 5

embedded image 4-[4-(N,N-diethylaminocarbonylmethyl)phenylmethyl]piperidine (1) Phenylacetic acid ethyl ester (68.6g)
and N-acetyl isonipecotic acid chloride (79.2 g) were added to dichloromethane (300 ml), anhydrous aluminum chloride (111 g) was gradually added, and the mixture was stirred at room temperature overnight. After adding the solution to ice water, the aqueous layer was further extracted with dichloromethane. After combining the dichloromethane layers and washing with water,
The mixture was dried over anhydrous magnesium sulfate, the solvent was distilled off, concentrated hydrochloric acid (400 ml) was added to the obtained oily compound, and the mixture was heated under reflux for 20 hours. After extraction with ethyl acetate, the aqueous layer is concentrated and left at room temperature to partially crystallize, and after adding ethanol and collecting by filtration, the aqueous layer has a melting point of 261-26.
6.3 g of colorless crystal 4-[(piperidin-4-yl)carbonylphenylacetic acid monohydrochloride at 4°C was obtained. (2) 6.1 g of 4-[(piperidin-4-yl)carbonyl]phenylacetic acid monohydrochloride obtained above was added to water (
40 ml) and concentrated hydrochloric acid (4 ml), followed by catalytic hydrogen reduction and tert-butyloxycarbonylation reaction in the same manner as in Example 1-(3) to obtain a colorless oily compound 1-tert-butyloxycarbonyl-4. -[4-(hydroxycarbonylmethyl)phenylmethyl]piperidine (5.3
g) was obtained. NMR (CDCl3): δ=0.9-1
．． 8 (5H, m), 1.43 (9H, s), 2.52 (
2H, d), 2.4-2.8 (2H, m), 3.62 (
2H, s), 3.9-4.2 (2H, m), 7.0-7
．． 4 (4H, m). (3) 1-tert-butyloxycarbonyl-4-[4
-(hydroxycarbonylmethyl)phenylmethyl]piperidine (3.3 g) in dimethylformamide (30 m
l) Diethylamine hydrochloride (1.1 g) and triethylamine (4.2 ml) were added to the solution, and diethyl cyanophosphate (2.5 ml) was added thereto, followed by stirring at room temperature for 2 hours. Hereinafter, a colorless oily compound, 1-tert-butyloxycarbonyl-4-
3.1 g of [4-(N,N-diethylaminocarbonylmethyl)phenylmethyl]piperidine was obtained. NMR (CDCl3): δ=0.9-1.8 (5H,
m), 1.06 (3H, t), 1.10 (3H, t),
1.46 (9H, s), 2.52 (2H, d), 2.4
~2.8 (2H, m), 3.28 (2H, q), 3.3
6 (2H, q), 3.65 (2H, s), 3.9-4.
2 (2H, m), 7.0-7.3 (4H, m). (4) 1-tert-butyloxycarbonyl-4-[4
-(N,N-diethylaminocarbonylmethyl)phenylmethyl]piperidine (3.0 g) was dissolved in trifluoroacetic acid (15 ml) and left at room temperature for 10 minutes. After trifluoroacetic acid was distilled off, 50 ml of water was added to the remaining oily compound, and the mixture was made basic with a 10% aqueous sodium hydroxide solution. After extraction with ethyl acetate, drying over anhydrous magnesium sulfate and distilling off the solvent, a colorless oily compound 4-[
4-(N,N-diethylaminocarbonylmethyl)phenylmethyl]piperidine (1.7 g) was obtained. NMR (CDCl3): δ=1.0-1.9 (5H,
m), 1.03 (3H, t), 1.08 (3H, t),
2.58 (2H, d), 2.7-3.0 (2H, m),
3.25 (2H, q), 3.35 (2H, q), 3.1
~3.5 (2H, m), 3.67 (2H, s), 7.1
~7.4 (4H, m).

Example 6

embedded image 4-[4-[2-(N,N-diethylamino)ethyl]
Phenylmethyl]piperidine dihydrochloride 4-[(4-diethylaminocarbonylmethyl)phenylmethyl]piperidine (1.5g) was dissolved in anhydrous tetrahydrofuran (20ml), and lithium aluminum hydride (0.51g) was added thereto at room temperature. Afterwards, the mixture was heated and stirred at 60°C for 2 hours. The reaction solution was returned to room temperature, and water (0.8 ml) and 10% aqueous sodium hydroxide solution (0.8 ml) were added to the reaction solution.
After adding 6 ml), the precipitate was filtered off. After adding 2N hydrogen chloride in dioxane solution (10 ml) to the mother liquor, the solvent was distilled off to obtain a colorless amorphous solid (1.35 g). Elemental analysis value: Calculated value as C18H32Cl2N2:
C, 62.24; H, 9.29; N, 8.0
6 Actual value: C, 62.10; H, 9.45; N
, 8.03NMR(D2O): δ=1.33(6H
, t), 1.2-2.1 (5H, m), 2.67 (2H
, d), 2.8-3.6 (8H, m), 3.30 (4H
, q), 7.2-7.5 (4H, m).

Example 7 The compounds shown in Table 1 were obtained by the same procedure as in Example 1.

[Table 1]

Example 8 From the compound of Example 7, by the same procedure as in Example 2,
The compounds shown in Table 2 were obtained.

[Table 2]

Example 9

embedded image 4-[4-(morpholinocarbonylmethyl)phenylmethyl]piperidine 1-tert-butyloxycarbonyl-4-[4-(hydroxycarbonylmethyl)phenylmethyl]piperidine (
3.47 g) in dimethylformamide (30 ml), morpholine (0.96 g) and triethylamine (2
．． 8 ml) and diethyl cyanophosphate (2.
After adding 5 ml), the mixture was stirred at room temperature for 2 hours. By the same operation as in Example 1-(4), colorless oily compound 1-
Tertiary-butyloxycarbonyl-4-[4-(morpholinocarbonylmethyl)phenylmethyl]piperidine 2.7
I got g. This was dissolved in trifluoroacetic acid (20 ml) and left at room temperature for 10 minutes. After distilling off trifluoroacetic acid, the remaining oily compound was added with a 10% aqueous sodium hydroxide solution (
After extraction with ethyl acetate, it was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain a colorless oily compound (1.6 g). NMR (CDCl3
): δ = 1.0 to 1.9 (5H, m), 2.61 (2
H, d), 2.7-3.1 (2H, m), 3.1-3.
8 (10H, m), 3.65 (2H, s), 7.1-7
．． 4 (4H, m).

Example 10

[Chemical formula 23] 4-[4-(2-morpholinoethyl)phenylmethyl]
Piperidine dihydrochloride 4-[4-(morpholinocarbonylmethyl)phenylmethyl]piperidine obtained in Example 9 (1.0 g
) and the same operation as in Example 6 to obtain a colorless amorphous solid (0.8 g). Elemental analysis value: Calculated value as C18H30Cl2N2O: C, 59.83; H, 8.37; N, 7.
75 actual value: C, 59.58; H, 8.10;
N, 7.53NMR (D2O): δ=1.1-2.
1 (5H, m), 2.61 (2H, d), 2.74 (2
H, t), 2.7-3.7 (14H, m), 7.1-7
．． 4 (4H, m).

Example 11

embedded image 1-diphenylmethyl-4-[4-(N,N-dimethylaminomethyl)phenylmethyl]piperidine dihydrochloride 4-[4-(N,N-dimethylaminomethyl) obtained in Example 2 ) phenylmethyl]piperidine dihydrochloride (1.5
g), bromodiphenylmethane (1.3 g), and solid potassium carbonate (1.38 g) were added to ethanol (30 ml), and the mixture was heated and stirred for 8 hours. After filtering off the insoluble matter, the solvent was distilled off, and the remaining oily compound was separated and purified by silica gel column chromatography (developing solvent: dichloromethane).The obtained oily compound was dissolved in ethanol, and 2N hydrogen chloride was added to it. An ethanol solution (1 ml) of . By distilling off the solvent, a colorless amorphous solid (1.
6g) was obtained. Elemental analysis value: Calculated value as C28H36Cl2N2:
C, 71.32; H, 7.70; N, 5.9
4 Actual measurements: C, 71.26; H, 7.65; N
, 5.74NMR (DMSO-d6+D2O): δ
=1.0-2.1 (5H, m), 2.65 (2H, d)
, 2.76 (6H, s), 2.8-3.5 (4H, m)
, 4.28 (2H, s), 4.48 (1H, s), 7.
0-7.6 (14H, m).

Example 12

1-Ethyl-4-[4-(N,N-diethylaminomethyl)phenylmethyl]piperidine dihydrochloride 4-[4-(N,N-diethylaminocarbonylmethyl) obtained in Example 5 phenylmethyl]piperidine (
1.44 g) and triethylamine (0.7 ml) were dissolved in dichloromethane (30 ml), and acetic anhydride (0.7 ml) was dissolved in dichloromethane (30 ml).
．． 61 g) was added thereto, and the mixture was stirred at room temperature for 10 hours. After the reaction was completed, the solvent was distilled off, and the remaining oily compound was dissolved in ethyl acetate (50 ml), washed with 1N hydrochloric acid and a saturated aqueous sodium bicarbonate solution, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the remaining oily compound was dissolved in anhydrous tetrahydrofuran (20 ml), lithium aluminum hydride (0.38 g) was added thereto, and the mixture was heated at 60°C for 1 hour.
Stir for hours. The reaction solution was returned to room temperature, and water (0.
63ml), 10% aqueous sodium hydroxide solution (0.47ml), 10% aqueous sodium hydroxide solution (0.47ml),
ml), the precipitate was filtered off. After distilling off the solvent, the remaining oily compound was purified by silica gel column chromatography (
Developing solvent: n-butanol: acetic acid: acetic acid ethyl ester: water 1:1:1:1 (v/v)
When the solvent is distilled off, a colorless amorphous solid (
0.9 g) was obtained. Elemental analysis value: Calculated value as C19H34Cl2N2:
C, 63.15; H, 9.48; N, 7.7
5 Experimental values: C, 62.98; H, 9.34; N
, 7.57NMR (D2O): δ=1.1-2.1
(5H, m), 1.32 (6H, t), 1.35 (6H
, t), 2.68 (2H, d), 2.8-3.2 (2H
, m), 3.20 (4H, q), 3.25 (2H, q)
, 3.3-3.7 (2H, m), 4.32 (2H, s)
, 7.3-7.5 (4H, m).

Example 13

embedded image 1-n-butyl-4-[4-(2-morpholinoethyl)
Phenylmethyl]piperidine dihydrochloride 4-[4-(morpholinocarbonylmethyl)phenylmethyl]piperidine (1.5 g) obtained in Example 9 and triethylamine (0.7 ml) were dissolved in dichloromethane (30 g) and triethylamine (0.7 ml).
ml) and add butyryl chloride (0.58 ml) to it.
was added and stirred at room temperature for 2 hours. Thereafter, in the same manner as in Example 11, a colorless amorphous solid (1.2 g) was obtained. Elemental analysis value: Calculated value as C22H38Cl2N2O: C, 63.29; H, 9.18; N, 6.
71 Experimental value: C, 63.18; H, 9.02;
N, 6.62NMR (D2O): δ=1.0-2.
1 (9H, m), 1.35 (3H, t), 2.64 (2
H, d), 2.74 (2H, t), 2.6-3.6 (1
6H, m), 7.1-7.4 (4H, m).

[0076]

[Test example] 1. Anti-cerebral ischemic effect A male Gerbil (Seiwa, 8-10 weeks old) was anesthetized with ether, and after a midline neck incision, bilateral common carotid arteries were ligated. After ligation for 15 minutes, reperfusion was performed. The survival rate was calculated 8 hours and 7 days after reperfusion. The test drug was intraperitoneally administered twice, 30 minutes before ligation and 90 minutes after reperfusion. The control group received physiological saline. (Table 3)

Table 3 From this table, it is clear that the compound (I) of the present invention or a salt thereof has excellent anti-cerebral ischemic activity.

2. Anti-cerebral edema effect A male rat (Wister/Jcl, 11 weeks old) was anesthetized with ether, the neck was incised, and the pterygopalatine artery and external carotid artery were ligated. After the common carotid artery blood flow was blocked, a cannula was retrogradely inserted from the external carotid artery and placed at the origin of the internal carotid artery. 20% carbon microspheres (diameter 50 ± 10 μm)
It was suspended in dextran and selectively injected into the internal carotid artery through a cannula over about 10 seconds. 72 hours after injection,
After the brain is removed, it is separated into the left and right cerebral hemispheres, and the water content and
The amount of sodium and ions were measured. The test drug was intraperitoneally administered twice a day, in the morning and afternoon, 30 minutes before and 5 hours after the microfere injection, and thereafter until the end of the experiment. 5% gum arabic was used for the control group. The results are shown in Table 4.

[Table 4] This table shows that the objective compound (I) of the present invention or a salt thereof treats cerebral edema by increasing the amount of sodium and decreasing the amount of potassium without changing the water content of the brain. It is clear that it has an excellent effect.

Formulation Example 1 (1) 4-[4-(N,N-diethylaminomethyl)phenyl 50 g
Methyl]piperidine dihydrochloride (Example 4 compound) (2) Lactose

198g (3) Corn starch
5
0g (4) Magnesium stearate

2g (1), (2) and 20g corn starch are mixed and granulated with a paste made from 15g corn starch and 25ml water, to which 15g corn starch and (4) are added and the mixture is compressed. Thus, 1000 tablets with a diameter of 5 mm and each tablet containing 50 mg of (1) were manufactured.

Formulation Example 2 4-[4-(N,N-diethylaminomethyl)phenylmethyl]piperidine dihydrochloride 2 g and mannitol 1
．． After dissolving 25g in water, p
After adjusting H to 5 to 7, the total volume is adjusted to 100 ml. This solution was filtered for sterilization through a 0.2 μm filter. This is 1
The mixture was dispensed into 100 ml ampoules.

[0080]

Effects of the Invention The cyclic amine compound (I) of the present invention and its salts exhibit strong anti-cerebral ischemic activity in gerbils, and anti-cerebral edema activity in rats, as revealed in the above test examples. showed that. Diseases for which the cyclic amine compound (I) and its salts of the present invention are useful include:
Examples include various symptoms associated with intracerebral hypoxia and cerebral ischemia, various symptoms associated with increased intracranial pressure due to intracerebral neoplasms and traumatic pressure, and diseases such as cerebral edema and dementia. (I) and its salts can be used for the prevention or treatment of these diseases. Therefore, the present invention provides a useful therapeutic agent for stroke sequelae, particularly a therapeutic agent for cerebral edema, an agent for improving cerebral microcirculation disorders (red blood cell deformability), and an agent for protecting brain and nerve cells.

Claims (4)

[Claims] Claim 1: Formula [Formula 1] [wherein R1 and R2 each represent a C1-5 alkyl group, or together with the adjacent nitrogen atom represent a cyclic amino group, R3 represents a hydrogen atom, a C1-5 alkyl group] group, phenyl-C1-5 alkyl group which may have a substituent, or diphenyl-C1-5 which may have a substituent
an alkyl group, X is a methylene group or a carbonyl group,
A cyclic amine compound or a salt thereof, wherein n is an integer of 0 to 4, and ring A represents a benzene ring which may have a substituent. [Claim 2] Formula [Formula 2] [wherein R1 and R2 each represent a C1-5 alkyl group, or together with adjacent nitrogen atoms represent a cyclic amino group, and X represents a methylene group or a carbonyl group, n
represents an integer of 0 to 4, and ring A represents a benzene ring which may have a substituent] or a salt thereof, and a compound represented by formula R3'-Z [wherein R3' is C1-5 An alkyl group, a phenyl-C1-5 alkyl group which may have a substituent, or a diphenyl-C1-5 alkyl group which may have a substituent, Z is fused with the hydrogen molecule at the 1-position of the piperidine ring. A cyclic amine compound represented by the formula [Chemical formula 3] [The symbols in the formula have the same meanings as above] or its Salt manufacturing method. Claim 3: Formula [Image Omitted] [In the formula, R1 and R2 each represent a C1-5 alkyl group, or together with the adjacent nitrogen atom represent a cyclic amino group, and R4 represents a hydrogen atom, a C1-5 alkyl group, group, a phenyl-C1-5 alkyl group which may have a substituent, a diphenyl-C1-5 alkyl group which may have a substituent or a formula R5-CO- (wherein, R5 is a hydrogen atom,
C1-4 alkyl group, phenyl-C1-4 alkyl group which may have a substituent or diphenyl-C1-4 alkyl group which may have a substituent), is an integer of 0 to 4, and ring A represents a benzene ring which may have a substituent.] [Formula 5] [In the formula, R3 is a hydrogen atom, a C1-5 alkyl group, a phenyl-C1-5 alkyl group that may have a substituent, or a diphenyl-C1-5 alkyl group that may have a substituent, and the other symbols are A method for producing a cyclic amine compound or a salt thereof represented by: [Claim 4] Formula [Image Omitted] [In the formula, R1 and R2 each represent a C1-5 alkyl group, or together with the adjacent nitrogen atom represent a cyclic amino group, and R3 represents a hydrogen atom, a C1-5 alkyl group, group, phenyl-C1-5 alkyl group which may have a substituent, or diphenyl-C1-5 which may have a substituent
An anti-cerebral edema agent containing a cyclic amine compound represented by an alkyl group, n is an integer of 0 to 4, and A ring represents a benzene ring which may have a substituent, or a salt thereof.